Research & Scholarship

Current Research and Scholarly Interests

As an academic orthopaedic surgeon, my interests center on adult reconstructive surgery including total joint replacement, osteotomies and the fixation of fractures. Both clinical and basic science investigations are ongoing.

My specific research interests include the following:

1. the biological aspects of the interface between orthopaedic implants/biomaterials and bone

Abstract

PURPOSE: The murine calvarial model has been widely employed for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening of total joint replacements. Classically, this model uses an open surgical technique in which polyethylene (PE) particles are directly spread over the calvarium for the induction of osteolysis. We evaluated a minimally invasive modification of the calvarial model by using a direct subcutaneous injection of PE particles. METHODS: Polyethylene (PE) particles were injected subcutaneously over the calvaria of C57BL6J ten-week-old mice ("injection" group) or were implanted after surgical exposure of the calvaria ("open" group) (n = 5/group). For each group, five additional mice received no particles and served as controls. Particle-induced osteolysis was evaluated two weeks after the procedure using high-definition microCT imaging. RESULTS: Polyethylene particle injection over the calvaria resulted in a 40 % ± 1.8 % decrease in the bone volume fraction (BVF), compared to controls. Using the "open surgical technique", the BVF decreased by 16 % ± 3.8 % as compared to controls (p

Abstract

Changes in T1ρ and T2 magnetic resonance relaxation times have been associated with articular cartilage degeneration, but similar relationships for meniscal tissue have not been extensively investigated. This work examined relationships between T1ρ and T2 measurements and biochemical and mechanical properties across regions of degenerate human menisci.Average T1ρ and T2 relaxation times were determined for nine regions each of seven medial and 13 lateral menisci from 14 total knee replacement patients. Sulfated glycosaminoglycan (sGAG), collagen and water contents were measured for each region. Biomechanical measurements of equilibrium compressive, dynamic compressive and dynamic shear moduli were made for anterior, central and posterior regions.T1ρ and T2 times showed similar regional patterns, with longer relaxation times in the (radially) middle region compared to the inner and outer regions. Pooled over all regions, T1ρ and T2 times showed strong correlations both with one another and with water content. Correlations with biochemical content varied depending on normalization to wet or dry mass, and both imaging parameters showed stronger correlations with collagen compared to sGAG content. Mechanical properties displayed moderate inverse correlations with increasing T1ρ and T2 times and water content.Both T1ρ and T2 relaxation times correlated strongly with water content and moderately with mechanical properties in osteoarthritic menisci, but not as strongly with sGAG or collagen contents alone. While the ability of magnetic resonance imaging (MRI) to detect early osteoarthritic changes remains the subject of investigation, these results suggest that T1ρ and T2 relaxation times have limited ability to detect compositional variations in degenerate menisci.

Abstract

Implants are widely used for orthopaedic applications such as fixing fractures, repairing non-unions, obtaining a joint arthrodesis, total joint arthroplasty, spinal reconstruction, and soft tissue anchorage. Previously, orthopaedic implants were designed simply as mechanical devices; the biological aspects of the implant were a byproduct of stable internal/external fixation of the device to the surrounding bone or soft tissue. More recently, biologic coatings have been incorporated into orthopaedic implants in order to modulate the surrounding biological environment. This opinion article reviews current and potential future use of biologic coatings for orthopaedic implants to facilitate osseointegration and mitigate possible adverse tissue responses including the foreign body reaction and implant infection. While many of these coatings are still in the preclinical testing stage, bioengineers, material scientists and surgeons continue to explore surface coatings as a means of improving clinical outcome of patients undergoing orthopaedic surgery.

Abstract

Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8?mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios.

Abstract

Joint replacement is an option that has demonstrated significant improvement in the quality of life for individuals with severe arthritis. However, it is often delayed either in an attempt to avoid future revision surgeries or for other personal reasons. Increasing disability leads to inactivity, chronic pain, and sleep disruption, each of which cycles into significant comorbid risks, many of which are life-threatening. A beginning conceptual framework identified as the cycle of comorbidities is presented to identify these risks and help guide both the patient and the provider in the decision-making process associated with joint replacement surgery.

Abstract

Total joint arthroplasty has revolutionized the treatment of arthritic and degenerative conditions for many joints in the body; however, wear debris is continuously generated with day-to-day use of an artificial joint. Excessive production of wear by-products induces a foreign body and chronic inflammatory reaction that accelerates periprosthetic bone destruction and inhibits bone formation. The specific biologic reaction is dependent on the type, amount, and characteristics of the by-products of wear, along with individual genetic variations. For polymeric and ceramic particles, the inflammatory reaction is generally nonspecific and nonimmune; however, with metallic by-products, a type IV, T lymphocyte-mediated, antigen-dependent immune reaction can occur in some patients. The production of proinflammatory cytokines, chemokines, reactive oxygen species, and other mediators is upregulated by wear particles. Animal models have shown that the biologic reaction to wear particles is systemic in nature, not a localized event. Mechanical stimuli and the presence of endotoxin also appear to be important. Efficacious biologic treatments of periprosthetic osteolysis are not yet available. Research continues with the hope that viable strategies for preventing and treating particle-induced osteolysis will be introduced in the future, thus mitigating the need for revision surgery.

Abstract

Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17β-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.

Abstract

Understanding how relevant cell types respond to wear particles will reveal new avenues for treating osteolysis following joint replacements. In this study, we investigate the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on preosteoblast migration and function. We infused UHMWPE particles or saline into the left femur of mice and injected luciferase-expressing preosteoblasts (MC3T3 cells) into each left ventricle. Bioluminescence imaging (BLI) confirmed systemic administration of MC3T3 cells. BLI throughout the 28-day experiment showed greater MC3T3 migration to the site of particle infusion than to the site of saline infusion, with significant differences on days 0, 4, and 6 (p?0.055). Immunostaining revealed a greater number of osteoblasts and osteoclasts in the particle-infused femora, indicating greater bone turnover. The bone mineralization of the particle-infused femora increased significantly when compared to saline-infused femora (an increase of 146.4±27.9 vs. 12.8±8.7?mg/mL, p=0.008). These results show that infused preosteoblasts can migrate to the site of wear particles. Additionally, as the migrated cells were associated with increased bone mineralization in spite of the presence of particles, increasing osteoblast recruitment is a potential strategy for combating bone loss due to increased osteoclast/macrophage number and decreased osteoblast function.

Abstract

Minimal incision total knee arthroplasty (MI TKA) was developed with the potential to decrease surgical trauma, pain, and recovery time. While this procedure has increased in popularity, some surgeons have questioned its safety and long-term efficacy. In this study 58 consecutive revision total knee arthroplasties (TKAs) (57 patients) performed at one academic medical center from 2006 to 2008 are reviewed. Prospectively collected clinical and radiographic data included: incision length, gender, age, time to revision surgery, and primary diagnosis at time of revision. Of these, 34 knees involving infection and rerevision were excluded. Of the remaining 24 knees, 11 knees that met inclusion criteria had undergone MI TKA. There were no differences between the groups with regard to age, diagnosis, body mass index, and gender. Average time to revision was shorter for the MI TKA patients (29 vs. 65 months, p < 0.032, odds ratio 14.7). Reasons for revision were aseptic loosening (55%), pain/stiffness (27%), malrotation (9%), and instability (9%) in the MI TKA group and aseptic loosening (53%), instability (15%), pain/stiffness (8%), malrotation (8%), combined malrotation and instability (8%), and polyethylene wear/osteolysis (8%) in the traditional TKA group. These data suggest that MI TKA may be a risk factor for early revision.

Abstract

Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

Abstract

With the institution of quality-assurance parameters in health care, physicians must accurately measure and report the true baseline rates of adverse events (AEs) after complex surgical interventions. To better quantify the risk of AEs for revision total hip arthroplasty (THA), we divided a cohort of 306 patients (322 procedures) into age groups: group I (<65 years, n = 138), group II (65-79 years, n = 119), and group III (?80 years, n = 65). Ninety-day rates of major AE were 9%, 19%, and 34% in the groups, respectively. Group III had an increased chance of experiencing major AE compared with groups I and II. Age and Charlson Comorbidity Index independently predicted major complications, whereas body mass index, sex, and type of revision did not.

Abstract

Currently, younger, more active patients are being offered total joint replacement (TJR) for end-stage arthritic disorders. Despite improved durability of TJRs, particle-associated wear of the bearing surfaces continues to be associated with particulate debris, which can activate monocyte/macrophages. Activated macrophages then produce pro-inflammatory factors and cytokines that induce an inflammatory reaction that activates osteoclasts leading to bone breakdown and aseptic loosening. We hypothesized that activated macrophages in tissues harvested from revised joint replacements predominantly express an M1 pro-inflammatory phenotype due to wear-particle-associated cell activation, rather than an M2 anti-inflammatory phenotype. We further questioned whether it is possible to convert uncommitted monocyte/macrophages to an M2 phenotype by the addition of interleukin-4 (IL-4), or whether it is necessary to first pass through an M1 intermediate stage. Retrieved periprosthetic tissues demonstrated increased M1/M2 macrophage ratios compared to non-operated osteoarthritic synovial tissues, using immunohistochemical staining and Western blotting. Uncommitted monocyte/macrophages with/without polymethyl-methacrylate particles were transformed to an M2 phenotype by IL-4 more efficiently when the cells were first passed through an M1 phenotype by exposure to endotoxin. Wear particles induce a pro-inflammatory microenvironment that facilitates osteolysis; these events may potentially be modulated favorably by exposure to IL-4.

Abstract

Particle-associated periprosthetic osteolysis remains a major issue in joint replacement. Ongoing bone loss resulting from wear particle-induced inflammation is accompanied by continued attempts at bone repair. Previously we showed that mesenchymal stem cells (MSCs) are recruited systemically to bone exposed to continuous infusion of ultra high molecular weight polyethylene (UHMWPE) particles. The chemokine-receptor axis that mediates this process is unknown. We tested two hypotheses: (1) the CCR1 receptor mediates the systemic recruitment of MSCs to UHMWPE particles and (2) recruited MSCs are able to differentiate into functional mature osteoblasts and decrease particle-associated bone loss. Nude mice were allocated randomly to four groups. UHMWPE particles were continuously infused into the femoral shaft using a micro-pump. Genetically modified murine wild type reporter MSCs were injected systemically via the left ventricle. Non-invasive imaging was used to assay MSC migration and bone mineral density. Bioluminescence and immunohistochemistry confirmed the chemotaxis of reporter cells and their differentiation into mature osteoblasts in the presence of infused particles. Injection of a CCR1 antagonist decreased reporter cell recruitment to the UHMWPE particle infusion site and increased osteolysis. CCR1 appears to be a critical receptor for chemotaxis of MSCs in the presence of UHMWPE particles. Interference with CCR1 exacerbates particle-induced bone loss.

Abstract

The host response to biomaterials has been studied for decades. Largely, the interaction of host immune cells, macrophages in particular, with implanted materials has been considered to be a precursor to granulation tissue formation, the classic foreign body reaction, and eventual encapsulation with associated negative impacts upon device functionality. However, more recently, it has been shown that macrophages, depending upon context dependent polarization profiles, are capable of affecting both detrimental and beneficial outcomes in a number of disease processes and in tissue remodeling following injury. Herein, the diverse roles played by macrophages in these processes are discussed in addition to the potential manipulation of macrophage effector mechanisms as a strategy for promoting site-appropriate and constructive tissue remodeling as opposed to deleterious persistent inflammation and scar tissue formation.

Abstract

Although iliac crest autologous bone graft remains the gold standard for treatment of bone defects, delayed- and nonunions, and arthrodeses, several alternative strategies have been attempted, including the use of mesenchymal stem cells. Whether cells from the osteoblast lineage demonstrate systemic recruitment to an acute bone defect or fracture, and whether these cells directly participate in bone healing is controversial. This study tests two hypotheses: (1) that exogenous murine MC3T3-E1 osteoprogenitor cells with a high propensity for osteoblast differentiation are able to systemically migrate to a bone defect and (2) that the migrated MC3T3-E1 cells enhance bone healing. Two groups of nude mice were used; a bone defect was drilled in the left femoral shaft in both groups. MC3T3-E1 were used as reporter cells and injected in the left ventricle of the heart, to avoid sequestration in the lungs. Injection of saline served as a control. We used bioluminescence and microCT to assay cell recruitment and bone mineral density (BMD). Immunohistochemical staining was used to confirm the migration of reporter cells. MC3T3-E1 cells were found to systemically migrate to the bone defect. Further, BMD at the defect was significantly increased when cells were injected. Systemic cell therapy using osteoprogenitor cells may be a potential strategy to enhance bone healing.

Abstract

The biological mechanisms leading to periprosthetic osteolysis involve both chemokines and the monocyte/macrophage cell lineage. Whether MCP-1 plays a major role in macrophage recruitment in the presence of wear particles is unknown. We tested two hypotheses: (1) that exogenous local delivery of MCP-1 induces systematic macrophage recruitment and (2) that blockade of the MCP-1 ligand-receptor axis decreases macrophage recruitment and osteolysis in the presence of ultra high molecular weight polyethylene (UHMWPE) particles. Six groups of nude mice were used. We used non-invasive imaging to assay macrophage recruitment and osteolysis. A murine macrophage cell line and primary wild type and CCR2 knockout murine macrophages were used as the reporter cells. Particles were infused into the femoral canal. Bioluminescence and immunohistochemical staining were used to confirm the migration of reporter cells. Locally infused MCP-1 induced systemic macrophage trafficking to bone. Injection of MCP-1 receptor antagonist significantly decreased reporter cell recruitment to bone infused with UHMWPE particles and decreased osteolysis. Systemic migration of reporter cells to infused particles was decreased when the reporter cells were deficient in the CCR2 receptor. Interruption of the MCP-1 ligand-receptor axis appears to be a viable strategy to mitigate trafficking of macrophages and osteolysis due to UHMWPE particles.

Abstract

The reconstruction of major acetabular bone defects during revision, conversion, and primary total hip arthroplasties (THAs) is challenging. We reviewed a consecutive series of 168 THAs (108 revisions, 8 conversions, and 52 primary THAs) performed by 1 surgeon (S.B.G.) between 1997 and 2008 using impaction bone grafting for acetabular reconstruction. Autograft, cancellous allograft croutons, and demineralized bone matrix were used to fill bone defects as needed. The acetabular bone deficiency was classified according to the American Academy of Orthopaedic Surgeons: type I, segmental deficiency with significant rim defect; type II, cavitary defects medially or posteriorly; type III, combined cavitary and segmental deficiency; type IV, pelvic discontinuity; and type V, arthrodesis. According to this method, 56 hips had type I, 31 hips had type II, 48 hips had type III, and 27 hips had type IV deficiencies. Of the 168 patients, 19 subsequently died of causes unrelated to the THA, and 11 were lost to follow-up. All patients had at least 2 years of follow-up. Average Harris Hip Score improved from 45.5±17.9 preoperatively to 81.1±16.5 postoperatively (P

Abstract

Highly cross-linked polyethylene (HXPE) in total hip arthroplasty has been shown to decrease wear rate compared with conventional liner. However, it has some disadvantages in that the mechanical properties cause early failure of the implant. This case report presents an unexpected failure of total hip arthroplasty in a 72-year-old woman that occurred at 20 months postsurgery. Operative findings revealed fracture of superior rim at locking groove of liner. We concluded that the failure was caused by decreased mechanical properties of highly cross-linked polyethylene, less thickness of polyethylene, more vertical cup, and use of large femoral head.

Abstract

Reconstruction of extensive bone defects remains technically challenging and has considerable medical and financial impact on our society. Surgical procedures often require a bone/substitute graft to enhance and accelerate bone repair. Bone autografts are associated with morbidity related to bone harvesting and are limited in quantity. Alternatively, bone allografts expose the patient to the risk of transmission of infectious disease. Synthetic bone graft substitutes, such as calcium sulfates, hydroxyapatite, tricalcium phosphate, and combinations, circumvent some of the disadvantages of auto- and allografts, but have limited indications. Biomedical research has made possible the stimulation of the body's own healing mechanisms, either by delivering exogenous growth factors locally, or by stimulating their local production by gene transfer. Among all known factors having osteoinductive properties, only two bone morphogenetic proteins (for specific indications) and demineralized bone matrix have been approved for clinical use. In addition, ongoing research is exploring the efficacy of cell therapy and tissue engineering. The present report examines the composition, biological properties, indications, clinical experience and regulations of several of the biotherapeutics employed for bone reconstruction.

Abstract

Ceramic on ceramic (COC) total hip arthroplasty (THA) was developed to reduce wear debris and accordingly, the occurrence of osteolysis and aseptic loosening especially in younger patients. Based on the excellent tribological behavior of current COC bearings and the relatively low biological activity of ceramic particles, significant improvement in survivorship of these implants is expected.We used manual search to identify all relevant studies reporting clinical data on COC THAs in PubMed. The objective was to determine whether current COC THA offers a better clinical outcome and survivorship than non-COC THA.Studies with early generation ceramic bearings yielded 68% to 84% mean survivorship at 20 years follow-up which is comparable with the survivorship of non-COC THAs. Studies on current ceramic bearings report a 10-year revision-free interval of 92% to 99%. These outcomes are comparable to the survivorship of the best non-COC THAs. However, there are still concerns regarding fracture of sandwich ceramic liners, squeaking, and impingement of the femoral neck on the rim of the ceramic liner leading to chipping, especially in younger and physically active patients.Current COC THA leads to equivalent but not improved survivorship at 10 years follow-up in comparison to the best non-COC THA. Based on this review, we recommend that surgeons weigh the potential advantages and disadvantages of current COC THA in comparison to other bearing surfaces when considering young very active patients who are candidates for THA.

Abstract

Many surgeons use acetabular components with constrained polyethylene liners to improve stability after total hip arthroplasty in patients with a history of hip dislocation. Surgical treatment is generally thought to be the only available option for the dislocated constrained liner. The success rate and clinical results of closed reduction for such patients is unclear. This report presents a case of a successful closed reduction of a dislocated constrained liner. Few papers have so far addressed closed reduction of a dislocated constrained liner. Furthermore, previous studies reported a variety of components. Publication of additional successful and unsuccessful case reports is therefore needed to help establish the optimal treatment protocol for a dislocated constrained liner.

Abstract

A randomized, prospective, comparative study was performed in 2 related, adjacent generation posterior stabilized total knee prostheses, to evaluate whether the newer design improved the clinical and radiographic outcome for treatment of advanced osteoarthritis of the knee. Ninety one total knee arthroplasties in 84 patients (45 Insall-Burstein II and 46 NexGen Legacy posterior stabilized [both from Zimmer, Warsaw, Ind] prostheses) with an average of 10.3 years of follow-up (range, 9-11.8 years) were included. The preoperative diagnoses were primary osteoarthritis in all patients. At the latest evaluation, there were no significant differences detected in the mean clinical and functional knee scores, average postoperative active range of motion, and anterior knee pain between the Insall-Burstein II and the NexGen Legacy groups postoperatively.

Abstract

The outcome and complications of 37 primary total hip arthroplasties by one surgeon in 24 patients with Charnley Class C juvenile idiopathic arthritis with up to 19.6 years follow-up are reported. Twenty-six femoral components were cementless; all acetabular components were cementless with screws. Age at operation averaged 22.6 years. Two patients (3 hips) have died. Twelve hips in 9 patients have failed. Six cementless acetabular components with conventional polyethylene were revised because of osteolysis after 5.5 to 14.5 years. All 3 cementless C2 femoral stems with minimal porous coating failed. One of eight cemented AML Bantam stems loosened at 3.5 years; 2 of 23 cementless AML Bantam stems loosened at 9.5 and 19.6 years. Pain relief and functional improvement are dramatic after total hip arthroplasty in juvenile idiopathic arthritis; however, the long-term outcome is guarded.

Abstract

This guideline supersedes a prior one from 2007 on a similar topic. The work group evaluated the available literature concerning various aspects of patient screening, risk factor assessment, and prophylactic treatment against venous thromboembolic disease (VTED), as well as the use of postoperative mobilization, neuraxial agents, and vena cava filters. The group recommended further assessment of patients who have had a previous venous thromboembolism but not for other potential risk factors. Patients should be assessed for known bleeding disorders, such as hemophilia, and for the presence of active liver disease. Patients who are not at elevated risk of VTED or for bleeding should receive pharmacologic prophylaxis and mechanical compressive devices for the prevention of VTED. The group did not recommend specific pharmacologic agents and/or mechanical devices. The work group recommends, by consensus opinion, early mobilization for patients following elective hip and knee arthroplasty. The use of neuraxial anesthesia can help limit blood loss but was not found to affect the occurrence of VTED. No clear evidence was established regarding whether inferior vena cava filters can prevent pulmonary embolism in patients who have a contraindication to chemoprophylaxis and/or known VTED.

Abstract

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

Abstract

In order to optimize and modulate bone formation it is essential to understand the expression patterns of key bone-specific growth factors, as osteoprogenitor cells undergo the processes of proliferation, differentiation and maturation. This study reports the sequential expression of bone-related growth and transcription factors when bone marrow-derived osteoprogenitor cells from C57BL mice were cultured on allograft bone discs. Mineralization and osteocalcin protein levels were used to track osteogenic differentiation and maturation. Bone-related growth factors, such as Bmp-2, Bmp-7, Ctnnb-1, Fgf-2, Igf-1, Vegf-a and Tgf-?1, and transcription factors, such as Runx-2 and osteocalcin, were examined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Total density of mineralized bone was significantly increased 7.6 ± 0.7% in allografts cultured with cells, compared with a 0.5 ± 2.0% increase in the controls without cells (p < 0.01). Osteocalcin protein levels peaked at day 4. Protein expression showed peaks of BMP-2 and TGF-?1 on day 2, with VEGF peaking on day 8, and IGF-1 decreasing on day 2. mRNA for Pdgf-a peaked on day 2; Bmp-2 on days 4 and 16; Ctnnb-1 on days 8 and 20; Vegf-a, Fgf-2, Runx-2 and Igf-1 on day 12; Tgf-?1 on day 16; and Pdgf-b on day 20. Osteogenic growth factors correlated with Runx-2 and Ctnnb-1, whereas a predominant vascular growth factor, Vegf-a, did not follow this pattern. Specific bone-related genes and proteins were expressed in a time-dependent manner when osteoprogenitor cells were cultured on cortico-cancellous bone discs in vitro.

Abstract

The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

Abstract

The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-? in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-? among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-?. Gene expression data indicated that this latter increase in TNF-? was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.

Abstract

Macrophages phagocytose metallic wear particles and produce mediators, which can induce cellular host response and aseptic implant loosening. Lipopolysaccharide (LPS) on the wear debris can stimulate macrophages via Toll-like receptor 4 (TLR4) and enhance the response. However, the precise functional role and interaction of TLRs and their adaptor molecules is still unclear. Rat bone marrow macrophages were stimulated with titanium particle (Ti) coated by LPS (Ti/LPS+) and LPS-free Ti (Ti/LPS-). mRNA levels of cytokines, TLRs and their adaptor molecules were measured using real time PCR. mRNA levels of TNF-?, IL-1?, and IL-6 increased in Ti/LPS+ than Ti/LPS-. In contrast, mRNA levels of TLR4, TLR5, and TLR9 decreased in Ti/LPS+ compared to Ti/LPS-. mRNA levels of MyD88, IRAK1, IRAK4 decreased gradually, and TRAF6 underwent an initial transient increase, followed by suppression in Ti/LPS+. However, mRNA levels of TLR2 and IRAK2 increased after phagocytosis of Ti/LPS+ than Ti/LPS-. The increased expressions of proinflammatory cytokines found in Ti/LPS+ indicated that their productions cytokines could be enhanced by phagocytosis of LPS-coated particles. Subsequent down-regulation of TLR4, TLR5, TLR9, MyD88, IRAK1, and IRAK4 suggests that self-protective mechanisms to regulate excessive host responses are activated in macrophages. Increase of TLR2 and IRAK2 and a transient increase of TRAF6 in Ti/LPS+ suggest that another possible pathway to modulate TLR-mediated cellular response to prolong inflammatory response in foreign body reaction of aseptic loosening. This down- and/or up-regulation of the potential TLR-mediated responses to LPS-coated particles reflects the proactive behavior of effector cells.

Abstract

To evaluate two magnetic resonance imaging (MRI) techniques, slice encoding for metal artifact correction (SEMAC) and multiacquisition variable-resonance image combination (MAVRIC), for their ability to correct for artifacts in postoperative knees with metal.A total of 25 knees were imaged in this study. Fourteen total knee replacements (TKRs) in volunteers were scanned with SEMAC, MAVRIC, and 2D fast spin-echo (FSE) to measure artifact extent and implant rotation. The ability of the sequences to measure implant rotation and dimensions was compared in a TKR knee model. Eleven patients with a variety of metallic hardware were imaged with SEMAC and FSE to compare artifact extent and subsequent patient management was recorded.SEMAC and MAVRIC significantly reduced artifact extent compared to FSE (P < 0.0001) and were similar to each other (P = 0.58), allowing accurate measurement of implant dimensions and rotation. The TKRs were properly aligned in the volunteers. Clinical imaging with SEMAC in symptomatic knees significantly reduced artifact (P < 0.05) and showed findings that were on the majority confirmed by subsequent noninvasive or invasive patient studies.SEMAC and MAVRIC correct for metal artifact, noninvasively providing high-resolution images with superb bone and soft tissue contrast.

Abstract

This study examined effects of intermittent hydrostatic pressure (IHP) and a chondrogenic growth factor, bone morphogenetic protein-2 (BMP-2), on anabolic, catabolic, and other metabolic markers in human osteoarthritic (OA) chondrocytes in vitro.Articular chondrocytes, isolated from femoral OA cartilage and maintained in high-density monolayer culture, were examined for effects of BMP-2 and IHP on gene expression of matrix-associated proteins (aggrecan, type II collagen, and SOX9) and catabolic matrix metalloproteinases (MMP-2 and MMP-3) and culture medium levels of the metabolic markers MMP-2, nitric oxide (NO), and glycosaminoglycan (GAG). The results were analyzed using a mixed linear regression model to investigate the effects of load and growth factor concentration.IHP and BMP-2 modulated OA chondrocyte metabolism in accordance with growth factor concentration independently, without evidence of synergism or antagonism. Each type of stimulus acted independently on anabolic matrix gene expression. Type II collagen and SOX9 gene expression were stimulated by both IHP and BMP-2 whereas aggrecan was increased only by BMP-2. IHP exhibited a trend to decrease MMP-2 gene expression as a catabolic marker whereas BMP-2 did not. NO production was increased by addition of BMP-2 and IHP exhibited a trend for increased levels. GAG production was increased by BMP-2.This study confirmed the hypothesis that human OA chondrocytes respond to a specific type of mechanical load, IHP, through enhanced articular cartilage macromolecule gene expression and that IHP, in combination with a chondrogenic growth factor BMP-2, additively enhanced matrix gene expression without interactive effects.

Abstract

Placental dysfunction underlies numerous complications of pregnancy. A major obstacle to understanding the roles of potential mediators of placental pathology has been the absence of suitable methods for tissue-specific gene manipulation and sensitive assays for studying gene functions in the placentas of intact animals. We describe a sensitive and noninvasive method of repetitively tracking placenta-specific gene expression throughout pregnancy using lentivirus-mediated transduction of optical reporter genes in mouse blastocysts.Zona-free blastocysts were incubated with lentivirus expressing firefly luciferase (Fluc) and Tomato fluorescent fusion protein for trophectoderm-specific infection and transplanted into day 3 pseudopregnant recipients (GD3). Animals were examined for Fluc expression by live bioluminescence imaging (BLI) at different points during pregnancy, and the placentas were examined for tomato expression in different cell types on GD18. In another set of experiments, blastocysts with maximum photon fluxes in the range of 2.0E+4 to 6.0E+4 p/s/cm(2)/sr were transferred. Fluc expression was detectable in all surrogate dams by day 5 of pregnancy by live imaging, and the signal increased dramatically thereafter each day until GD12, reaching a peak at GD16 and maintaining that level through GD18. All of the placentas, but none of the fetuses, analyzed on GD18 by BLI showed different degrees of Fluc expression. However, only placentas of dams transferred with selected blastocysts showed uniform photon distribution with no significant variability of photon intensity among placentas of the same litter. Tomato expression in the placentas was limited to only trophoblast cell lineages.These results, for the first time, demonstrate the feasibility of selecting lentivirally-transduced blastocysts for uniform gene expression in all placentas of the same litter and early detection and quantitative analysis of gene expression throughout pregnancy by live BLI. This method may be useful for a wide range of applications involving trophoblast-specific gene manipulations in utero.

Abstract

The regenerative potential of injured adult tissue suggests the physiological existence of cells capable of participating in the reparative process. Recent studies indicate that stem-like cells residing in tissues contribute to tissue repair and are replenished by precursor bone marrow-derived cells. Mesenchymal stromal cells (MSC) are among the candidates for reparative cells. These cells can potentially be mobilized into the circulation in response to injury signals and exert their reparative effects at the site of injury. Current therapies for musculoskeletal injuries pose unavoidable risks which can impede full recovery. Trafficking of MSC to the injury site and their subsequent participation in the regenerative process is thought to be a natural healing response that can be imitated or augmented by enhancing the endogenous MSC pool with exogenously administered MSC. Therefore, a promising alternative to the existing strategies employed in the treatment of musculoskeletal injuries is to reinforce the inherent reparative capacity of the body by delivering MSC harvested from the patient's own tissues to the site of injury. The aim of this review is to inform the reader of studies that have evaluated the intrinsic homing and regenerative abilities of MSC, with particular emphasis on the repair of musculoskeletal injuries. Research that supports the direct use of MSC (without in vitro differentiation into tissue-specific cells) will also be reported. Based on accruing evidence that the natural healing mechanism involves the recruitment of MSC and their subsequent reparative actions at the site of injury, as well as documented therapeutic response after the exogenous administration of MSC, the feasibility of the emerging strategy of instant stem-cell therapy will be proposed.

Abstract

The objective of this study is to determine a protocol for collecting acid-fast bacilli (AFB) and fungal intraoperative cultures during orthopedic procedures. An observational study was undertaken. Four hundred forty-six AFB cultures and 486 fungal cultures were processed over a 2-year period. The number of positive cultures was determined. A protocol specific to handling these types of specimens was developed. Cost analysis was completed to determine both the time and money saved if the new protocol was implemented. The infrequency of positive AFB and fungal cultures in this study suggests that it is only necessary to routinely request AFB and fungal cultures on 1 of 5 samples. Implementation of this protocol has potential to lead to substantial cost reduction and resource savings without diminishing patient outcomes.

Abstract

Patients with common variable immunodeficiency can present with debilitating arthritis. We present the case of a 42-year-old man with bilateral knee arthritis who underwent a right total knee arthroplasty that subsequently became infected. Five months after resection arthroplasty, his right leg spontaneously fused in extension, but his left knee was limited to an arc of motion between 90° and 110°. At the patient's request, he underwent a noninstrumented arthrodesis of the left knee. The patient now has bilateral arthrodeses and ambulates with a cane. While arthroplasty may be attempted in such patients, the increased risk of infection may potentially result in arthrodesis, possibly without instrumentation.

Abstract

Wear particles generated from total joint arthroplasty (TJA) stimulate macrophages to release chemokines. The role of chemokines released from wear particle-stimulated macrophages on the migration of macrophages and osteoprogenitor cells in vitro has not been elucidated. In this study, we challenged murine macrophages (RAW 264.7) with clinically relevant polymethyl methacrylate (PMMA, 1-10 microm) and ultra high molecular weight polyethylene (UHMWPE, 2-3 microm) particles. The chemotactic effects of the conditioned media (CM) were tested in vitro using human macrophages (THP-1) and human mesenchymal stem cells (MSCs) as the migrating cells. CM collected from both particle types had a chemotactic effect on human macrophages, which could be eliminated by monocyte chemotactic protein-1 (MCP-1) neutralizing antibody. Blocking the CCR1 receptor eliminated the chemotactic effect, while CCR2 antibody only partially decreased THP-1 cell migration. CM from PMMA but not UHMWPE-exposed macrophages led to chemotaxis of MSCs; this effect could be eliminated by macrophage inflammatory protein-1 alpha (MIP-1alpha) neutralizing antibody. Neither CCR1 nor CCR2 blocking antibodies showed an effect on the migration of MSCs. Chemokines released by macrophages stimulated by wear particles can have an effect on the migration of macrophages and MSCs. This effect seems to be dependent on the particle type, and may be modulated by MCP-1 and MIP-1alpha, however, more than one chemokine may be necessary for chemotaxis.

Abstract

Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

Abstract

Minimal incision total hip arthroplasty (MI THA) techniques were developed to decrease postoperative pain and recovery time. Although these techniques have increased in popularity, the long-term survivorship of these procedures is unknown.We therefore investigated whether the time to revision in our referral practice was shorter for patients who underwent primary MI THA compared to primary traditional THA.We retrospectively reviewed 46 revision THAs performed during a 3-year period. We excluded revisions performed for infection and rerevisions. Patients with incisions less than or equal to 10 cm were defined as having had MI THA. Fifteen of the 46 patients (33%) had undergone primary MI THA. At the time of primary index THA, the mean ages of the MI and non-MI patients were 65 years and 55 years, respectively.The mean time to revision was 1.4 years for the MI patients compared with 14.7 years for the non-MI patients. Twelve of the 15 patients having MI THA required revision within 2 years of primary THA compared to 4 of the 31 patients without MI surgery (OR = 26.5, 95% CI 4.4-160.0). There were no differences between the groups with regard to age, gender, or body mass index. The most common reasons for revision in the MI THA group were intraoperative fracture and failure of femoral component osseointegration.Our data suggest MI THA may be a risk factor for early revision surgery and the long-term survival therefore may be lower than that for non-MI surgery.Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Abstract

Excessive wear debris, deep infection, periprosthetic fracture, and other causes can lead to bone loss associated with total joint replacements. When performing revisions, surgeons are often preoccupied by the failed implant and the method of replacement, and neglect an opportunity to replenish lost bone. Thus, when formulating a plan for revision total joint replacement, the surgeon should consider not only the hardware that should be used, but also ways in which lost bone could be restored. Autograft bone provides the best source for osteoprogenitor cells, growth factors, and a scaffold. However, autograft is limited in supply, and is generally associated with another incision, dissection, and accompanying morbidity. Osteoconductive bone void fillers such as morselized cancellous allograft bone, polymeric scaffolds, and biodegradable ceramics each have their merits and deficiencies; however, all of these materials function as a scaffold only, without the ability to induce bone formation. Osteoinductive growth factors are essential to bone growth and remodeling; however, exogenous growth factors are expensive, are given in large nonphysiological doses, may yield unpredictable clinical results, and may have significant adverse effects. Demineralized bone matrix contains a scaffold and variable amounts of several growth factors. Recently, the use of mesenchymal stem cells and osteoprogenitors, together with a suitable scaffold carrier has gained increasing popularity. With the addition of appropriate growth factors, this combination can provide all the necessary components for osteogenesis. Future basic and clinical research will define the indications and outcomes for new combination products for reconstruction of lost bone associated with revision total joint replacement.

Abstract

Growth factors control the proliferation and differentiation of osteoprogenitor cells. This study explores the effects of modulating growth factors (VEGF, IGF-1, FGF-2 and BMP-2) on osteogenesis of mesenchymal stem cells (MSCs) in vitro. Constant and profiled delivery protocols, in accordance with protein expression in vitro, were applied to deliver or neutralize growth factors. Cell number, alkaline phosphatase (ALP-2) and osteocalcin (OC) expression, and mineralization were measured as outcome variables. Profiled addition of VEGF increased MSC proliferation. Constant and profiled application of FGF-2 and neutralization of IGF-1 and BMP-2 decreased ALP-2 levels. Profiled addition of BMP-2 vastly increased OC release from MSCs, but constant addition of IGF-1, constant and profiled neutralization of IGF-1 and FGF-2 reduced OC levels. Constant addition of IGF-1 and FGF-2, as well as profiled loading of FGF-2 decreased mineralization of MSCs. This study indicated that endogenous IGF-1 and FGF-2 are essential to osteogenesis; excess IGF-1 and FGF-2 were inhibitory to bone formation. Selective, temporally specific addition of growth factors, such as BMP-2 and VEGF appears to be an important strategy to enhance osteogenesis.

Abstract

Polymethylmethacrylate (PMMA) particles have been shown to inhibit the differentiation, proliferation, and mineralization of osteoprogenitor cells in vitro. In this study, we investigated the effects of OP-1 (BMP-7) on the osteogenesis of MC3T3-E1 osteoprogenitor cells exposed to PMMA particles in vitro. MC3T3-E1 cells challenged with PMMA particles on the 1st day of differentiation in osteogenic culture showed a significant dose-dependent decrease in mineralization and alkaline phosphatase expression over a 20-day culture period. Exposure of these cells to OP-1 (200 ng/mL) during days 1-4, 1-20, and 4-20 in the presence of PMMA particles resulted in significant increases in mineralization and alkaline phosphatase expression at all particle doses. Addition of OP-1 to MC3T3-E1 cultures challenged with PMMA particles on the 4th day of differentiation in osteogenic media also resulted in significant increases in mineralization and alkaline phosphatase expression. This study has shown that OP-1 stimulates osteogenesis in MC3T3-E1 osteoprogenitor cells that have been inhibited by PMMA particles. Local administration of OP-1 to the site of osteolysis may be a potential adjunctive therapy to reverse the bone destruction due to wear particles.

Abstract

This study examined the hypothesis that tensile strain and fluid flow differentially influence osteoarthritic human chondrocyte metabolism. Primary high-density monolayer chondrocytes cultures were exposed to varying magnitudes of tensile strain and fluid-flow using a four-point bending system. Metabolic changes were quantified by real-time PCR measurement of aggrecan, IL-6, SOX-9, and type II collagen gene expression, and by determination of nitric oxide levels in the culture medium. A linear regression model was used to investigate the roles of strain, fluid flow, and their interaction on metabolic activity. Aggrecan, type II collagen, and SOX9 mRNA expression were negatively correlated to increases in applied strain and fluid flow. An effect of the strain on the induction of nitric oxide release and IL-6 gene expression varied by level of fluid flow (and visa versa). This interaction between strain and fluid flow was negative for nitric oxide and positive for IL-6. These results confirm that articular chondrocyte metabolism is responsive to tensile strain and fluid flow under in vitro loading conditions. Although the articular chondrocytes reacted to the mechanically applied stress, it was notable that there was a differential effect of tensile strain and fluid flow on anabolic and catabolic markers.

Abstract

The destruction of bone around joint replacements (periprosthetic osteolysis) is an adverse biological response associated with the generation of excessive wear particles. Wear debris from the materials used for joint replacements stimulate a chronic inflammatory and foreign body reaction that leads to increased osteoclast differentiation and maturation, and decreased bone formation. Wear debris induces both local and systemic trafficking of inflammatory cells to the site of particle generation. Recent studies have shown that this effect is mediated primarily by chemotactic cytokines (chemokines) including macrophage chemotactic protein-1 (MCP-1, also known as CCL2), macrophage inhibitory protein-1 (MIP-1), Interleukin-8 (IL-8 or CXCL8) and others. These ligands migrate along a concentration gradient to interact with G-protein-linked transmembrane receptors on the cell surface. Chemokines are involved in the innate and adaptive immune responses, angiogenesis, wound healing and tissue repair. In vitro, in vivo and tissue retrieval studies have shown that chemokine-directed systemic trafficking of polymorphonuclear leukocytes and cells of the monocyte/macrophage lineage to wear particles result in the release of pro-inflammatory factors and subsequent bone loss. Modulation of the chemokine ligand-receptor axis is a potential strategy to mitigate the adverse effects of wear particles from joint replacements.

Abstract

Periprosthetic osteolysis of joint replacements caused by wear debris is a significant complication of joint replacements. Polymethylmethacrylate (PMMA) particles have been shown to inhibit osteogenic differentiation, but the molecular mechanism has not been previously determined. In this study, we exposed differentiating MC3T3-E1 preostoblast cells to PMMA particles and determined the changes that occurred with respect to p38 mitogen-activated protein kinase (MAPK) activity and the transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP) signaling pathways. In the absence of particles, MC3T3-E1 cells demonstrate activation of p38 MAPK on day 8 of differentiation; however, when treated with PMMA particles, differentiating MC3T3-E1 cells demonstrate the suppression of p38 activity on day 8 and show activation of p38 on days 1 and 4. On day 4 of particle exposure, the differentiating MC3T3-E1 cells show significant downregulation of TGF-beta1 expression, which is involved in osteoblast differentiation, and a significant upregulation of the expression of BMP3 and Sclerostin (SOST), which are negative regulators of osteoblast differentiation. By day 8 of particle exposure, the changes in TGF-beta1, BMP3, and SOST expression are opposite of those seen on day 4. This study has demonstrated the distinct changes in the molecular profile of MC3T3-E1 cells during particle-induced inhibition of osteoblast differentiation. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

Abstract

The management of the patella during revision total knee arthroplasty (TKA) depends on the indication for revision, the type and stability of the patellar component in place, and availability of bone stock. We prospectively compared the clinical outcome and satisfaction rates in revision TKA patients managed with patellar resurfacing (n = 13, group I) to retention of the patellar component (n = 22, group II) or patelloplasty (n = 11, group III) at a minimum follow-up of 2 years. There were no differences in the improvement of Knee Society Scores, Short-Form 36 Scores, and satisfaction rates between the groups. There were no revision surgeries for patellar component failure or patellar fractures. Satisfactory results can be achieved using a variety of methods of patellar management in revision TKA by individualizing the treatment modality depending on the clinical scenario.

Abstract

We prospectively compared the clinical outcomes and patient satisfaction rates of aseptic (n=30) versus septic revision TKA (n=15) at a mean follow-up of 40 months. We hypothesized that the clinical results of septic revision TKA would be inferior to aseptic revision TKA. The indication for revision in aseptic group was stiffness in 11 patients, aseptic loosening in 13, patellar loosening or maltracking in 6 patients. Patients operated for infection had better post-operative Knee Society Scores (KSS), Function Scores and SF-36 Mental Scores than aseptic group but there were no significant differences in the satisfaction rates. Patients operated for infection had more improvement in their KSS (p=0.004) and Function Scores (p=0.02) than patients revised for stiffness. Moreover, patients operated on for patellar problems had higher satisfaction rates than patients revised for stiffness (p=0.01) or aseptic loosening (p=0.01). Thus, patients undergoing septic revision TKA had better outcomes compared to those with aseptic revision TKA. However, in the aseptic group, revision TKA for stiffness was associated with the poorest outcomes. The indication for aseptic revision is an important variable when discussing treatment and outcome with patients.

Abstract

Polymethylmethacrylate (PMMA) particles have been shown to inhibit the differentiation of osteoprogenitor cells, but the mechanism of this inhibitory effect has not been investigated. We hypothesize that the inhibitory effects of PMMA particles involve impairment of osteoprogenitor viability and direct inhibition of transcription factors that regulate osteogenesis. We challenged MC3T3-E1 osteoprogenitors with PMMA particles and examined the effects of these materials on osteoprogenitor viability and expression of transcription factors Runx2, osterix, Dlx5, and Msx2. MC3T3-E1 cells treated with PMMA particles over a 72-h period showed a significant reduction in cell viability and proliferation as indicated by a dose- and time-dependent increase in supernatant levels of lactate dehydrogenase, an intracellular enzyme released from dead cells, a dose-dependent decrease in cell number and BrdU uptake, and the presence of large numbers of positively labeled Annexin V-stained cells. The absence of apoptotic cells on TUNEL assay indicated that cell death occurred by necrosis, not apoptosis. MC3T3-E1 cells challenged with PMMA particles during the first 6 days of differentiation in osteogenic medium showed a significant dose-dependent decrease in the RNA expression of Runx2, osterix, and Dlx5 on all days of measurement, while the RNA expression of Msx2, an antagonist of Dlx5-induced osteogenesis, remained relatively unaffected. These results indicate that PMMA particles impair osteoprogenitor viability and inhibit the expression of transcription factors that promote osteoprogenitor differentiation.

Abstract

Hydrogel polymers comprise a novel category of synthetic materials being investigated for use in cartilage replacement. One candidate compound, a poly(ethylene glycol)/poly(acrylic acid) (PEG/PAA) interpenetrating polymer network (IPN), was developed for use in corneal prostheses and was recently engineered for potential orthopedic use. The current study examined the effects of particles of this compound on two cell lines (MG-63 osteoblast-like cells and RAW 264.7 macrophages) over a 48-h time course. To mimic the effects of wear debris, particles of the compound were generated and introduced to the cells. In the MG-63 cell line, the particles had no significant effect on cell viability measured by PicoGreen assay and trypan blue exclusion. In contrast, a significant decrease in cell viability was detected in the Raw 264.7 macrophage cells at the final timepoint with the highest concentration of hydrogel (3.0% v:v). A concentration- and time-dependent increase in TNF-alpha release characteristic of other known biocompatible materials was also detected in RAW 264.7 cells, but nitric oxide and interleukin (IL)-1beta showed no response. In addition, the MG-63 cell line demonstrated no IL-6 response. Particles of the PEG/PAA IPN thus seem to stimulate biological responses similar to those in other biocompatible materials.

Abstract

Osteopontin (OPN) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatoid arthritis (RA). OPN can be cleaved by thrombin, resulting in OPN-R and exposing the cryptic C-terminal alpha4beta1 and alpha9beta1 integrin-binding motif (SVVYGLR). Thrombin-activatable carboxypeptidase B (CPB), also called thrombin-activatable fibrinolysis inhibitor, removes the C-terminal arginine from OPN-R, generating OPN-L and abrogating its enhanced cell binding. We undertook this study to investigate the roles of OPN-R and OPN-L in synoviocyte adhesion, which contributes to the formation of invasive pannus, and in neutrophil survival, which affects inflammatory infiltrates in RA.Using specifically developed enzyme-linked immunosorbent assays, we tested the synovial fluid of patients with RA, osteoarthritis (OA), and psoriatic arthritis (PsA) to determine OPN-R, OPN-L, and full-length OPN (OPN-FL) levels.Elevated levels of OPN-R and OPN-L were found in synovial fluid samples from RA patients, but not in samples from OA or PsA patients. Increased levels of OPN-R and OPN-L correlated with increased levels of multiple inflammatory cytokines, including tumor necrosis factor alpha and interleukin-6. Immunohistochemical analyses revealed robust expression of OPN-FL, but only minimal expression of OPN-R, in RA synovium, suggesting that cleaved OPN is released into synovial fluid. In cellular assays, OPN-FL, and to a lesser extent OPN-R and OPN-L, had an antiapoptotic effect on neutrophils. OPN-R augmented RA fibroblast-like synoviocyte binding mediated by SVVYGLR binding to alpha4beta1, whereas OPN-L did not.Thrombin activation of OPN (resulting in OPN-R) and its subsequent inactivation by thrombin-activatable CPB (generating OPN-L) occurs locally within inflamed joints in RA. Our data suggest that thrombin-activatable CPB plays a central homeostatic role in RA by regulating neutrophil viability and reducing synoviocyte adhesion.

Abstract

Pain following total hip arthroplasty due to impingement of the iliopsoas is a recognized complication of the procedure with a reported incidence as high as 4.3%. The pain is most often due to direct mechanical irritation of the iliopsoas due to a malpositioned or oversized acetabular cup. Definitive treatment of iliopsoas impingement often requires surgical revision or iliopsoas tenotomy, although many cases remain undiagnosed or are managed conservatively. We present an unusual case of pain after total hip arthroplasty due to a large retroperitoneal hematoma secondary to acetabular cup irritation of the iliopsoas tendon. This case represents a potentially important complication of undiagnosed or conservatively managed iliopsoas impingement, particularly in patients taking anticoagulants or antiplatelet medications.

Abstract

Total joint replacement is one of the most clinically successful, cost-effective surgical procedures. These operations have been shown to improve pain, function and mobility in patients with end-stage arthritis. However, joint replacements that will allow full, unrestricted, high impact activities and last the patient's lifetime have not yet been devised. This is due to biocompatibility issues related to material science, biomechanics, and host responses. In this review, three issues that are highly pertinent to biocompatibility of joint replacements are examined. These topics include how implants initially osseointegrate within bone, potential adverse effects of byproducts of wear that can lead to aseptic loosening and periprosthetic osteolysis, and the potential for new bearing surfaces to extend the lifetime of implants. A clear understanding of these important issues will facilitate the development of novel strategies to improve the longevity and function of implants for joint replacement in the future.

Abstract

Prosthetic cost contributes greatly to the overall expense of THA. A key question, therefore, in the selection of implant technique is whether any price difference exists between a cementless and a cemented femoral prosthesis. We evaluated the price difference between the most commonly used cemented and cementless femoral stems at three high-volume academic medical centers. Each hospital's costs for prostheses from the manufacturers were recorded. The average cost of implanting a cementless femoral prosthesis was $296 more than the average cost of implanting a cemented femoral stem, even with the additional expense of two batches of bone cement and the accessories commonly used to achieve a third-generation cementing technique. The price difference was less variable if the cost of the prostheses from only the primary implant supplier for each institution was considered. As the number of THAs performed per year continues to escalate, implantation of a cemented femoral component remains an attractive method of fixation from an economic standpoint. Level of Evidence: Level III, economic and decision analysis. See the Guidelines for Authors for a complete description of levels of evidence.

Abstract

The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.

Abstract

Conventional porous-coated joint prostheses used in hip and knee reconstruction have demonstrated good clinical results, however, these implants possess some inherent shortcomings such as low volumetric porosity, suboptimal frictional characteristics, and higher modulus of elasticity relative to that of bone. Porous tantalum, a novel porous biomaterial was developed to address these limitations. Extensive laboratory studies have revealed that porous tantalum has physical, mechanical and tissue in growth properties that makes it a potentially improved biomaterial particularly in complex joint reconstructions. Porous tantalum is a highly porous biomaterial with good biocompatibility, excellent corrosion resistance, and high coefficient of friction. The short term clinical results of porous tantalum in primary hip, revision hip, and knee reconstructive surgery are encouraging but further studies will be needed to determine whether the theoretical advantages of porous tantalum can provide long term biological fixation and stability. This review presents the biomaterial properties and clinical results of porous tantalum devices in hip and knee reconstructive surgeries.

Abstract

The concept of bone tissue engineering, which began in the early 1980s, has seen tremendous growth in the numbers of research studies. One of the key areas of research has been in the field of mesenchymal stem cells, where the challenge is to produce the perfect tissue-engineered bone construct. This practical review summarizes basic and applied state-of-the-art research in the area of mesenchymal stem cells, and highlights the important translational research that has already been initiated. The topics that will be covered include the sources of stem cells in use, scaffolds, gene therapy, clinical applications in nonunions, tumors, osteonecrosis, revision arthroplasties, and spine fusion. Although significant challenges remain, there exists an exceptional opportunity to translate basic research in mesenchymal stem cell technologies into viable clinical treatments for bone regeneration.

Abstract

Polyethylene wear debris induces progressive osteolysis by increasing bone degradation and suppressing bone formation. Polyethylene particles inhibit the function of mature osteoblasts, but whether polyethylene particles also interfere with the proliferation and differentiation of osteoprogenitor cells is unknown. In this study, we investigated the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on the osteogenic activity of primary murine bone marrow osteoprogenitors and MC3T3-E1 preosteoblastic cells in vitro. Submicron-sized UHMWPE particles generated from wear simulator tests were isolated from serum-containing solution by density gradient centrifugation. The particles were coated onto the surface of culture wells at concentrations of 0.038, 0.075, 0.150, 0.300, and 0.600% v/v in a layer of type I collagen matrix. Primary murine bone marrow cells and MC3T3-E1 preosteoblasts were seeded onto the particle-collagen matrix and induced to differentiate in osteogenic medium for 20 days. Exposure of both cell populations to UHMWPE particles resulted in a dose-dependent decrease in mineralization, proliferation, alkaline phosphatase activity, and osteocalcin production when compared with control cells cultured on collagen matrix without particles. Complete suppression of osteogenesis was observed at particle concentrations > or =0.150% v/v. This study demonstrated that UHMWPE particles inhibit the osteogenic activity of osteoprogenitor cells, which may result in reduced periprosthetic bone regeneration and repair.

Abstract

Toll-like receptors (TLR) are transmembrane proteins found in various cells. They recognize infectious and endogenous threats, so-called danger signals, that evoke inflammation and assist adaptive immune reactions. It has been suggested that TLR play a role in periprosthetic tissues and arthritic synovium. Our objective was to elucidate tissue localization and functional roles of TLR in periprosthetic tissues in 2 different pathologic conditions, aseptic and septic implant loosening.For immunohistochemistry studies, aseptic synovial-like membranes of periprosthetic connective tissues (n = 15) and septic synovial capsular tissues (n = 5) were obtained at revision surgery and from salvage of infected totally replaced hips, respectively. Osteoarthritic synovial tissues were used for comparison (n = 5). Samples were processed for immunohistopathologic analyses for tissue colocalization of TLR with CD68 and/or CD15 using the Alexa fluorescent system. Total RNA was isolated from frozen tissues and converted into cDNA, TLR 2, 4, 5 and 9 sequences were amplified, and the products were quantified using real-time polymerase chain reaction.Immunofluorescent staining showed colocalization of TLR 2, 4, 5, and 9 with CD68 in the focal monocyte/macrophage aggregates in aseptic synovial-like membranes from loose total hip replacements. TLR 2, 4, 5, and 9 were also found colocalized with CD15+ polymorphonuclear leukocytes and CD68+ mononuclear cells of the synovial membranes from septic total hip replacements. In osteoarthritic synovial tissues, expression of TLR was found only in vascular cells and mononuclear cells, and the reactivity was weak. mRNA levels of TLR 2, 4, 5, and 9 were increased in both aseptic and septic periprosthetic tissues. TLR 2 and 5 were significantly higher than TLR 4 and 9 in aseptic and septic samples.Peri-implant tissues were well equipped with TLR in both aseptic and septic conditions. TLR 2- and TLR 5-mediated responses seemed to dominate. In aseptic loosening, monocytes/ macrophages were the main TLR-equipped cells apparently responsible for alarmin-induced responses. This could lead to production of inflammatory cytokines and extracellular matrix-degrading proteinases after phagocytosis of wear debris derived from an implant, but in septic cases they eventually respond to microbial components. Thus, inflammatory cells in both aseptic and septic tissues were equipped with TLR, providing them with responsiveness to both endogenous and exogenous TLR ligands.

Abstract

Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [(18)F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [(18)F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p < 0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route.

Abstract

Constrained acetabular liners were developed for the surgical treatment of recurrent instability by holding the femoral head captive within the socket. This article summarizes the data describing constrained component designs, indications, outcome, and complications. Different designs accept head sizes of varying diameter and have differing amounts of rim elevation and offset, allowing slight variations in the range of movement allowed. Complications of constrained acetabular components can be divided into three categories. The first category is directly related to the constraining mechanism such as dislocation, head dissociation from the stem, liner dissociation from the acetabular device, and impingement with or without locking ring breakage. The second category is related to increased constraint such as aseptic component loosening and osteolysis and periprosthetic fracture. The third category includes those cases not associated with increased constraint such as infection, deep vein thrombosis, and periprosthetic fracture. This device is effective at achieving hip stability, but the complications related to the constraining mechanism and increased constraint are of concern. These devices should be used as a salvage measure for the treatment of severe instability.

Abstract

We evaluated the accuracy and clinical usefulness of preoperative templating in 109 cementless total hip arthroplasties. The size of the prosthesis was exactly predicted in 46 (42.2%) acetabular and 75 (68.8%) femoral components. The accuracy increased to greater than 90% if the prosthesis size was within 1 or 2 sizes (above or below) for femoral component and acetabular components, respectively. Having a contralateral total hip arthroplasty as a guide for preoperative templating was associated with greater accuracy in predicting the femoral component size only. Eighty-eight percent of the acetabular components were oriented inside the presumed safe range for inclination; 42% of the acetabular components were in the presumed safe range of anteversion. The mean postoperative leg length discrepancy was 0.9 +/- 6.8 mm; 93.5% had a discrepancy within 10 mm.

Abstract

Continued production of wear debris affects both initial osseointegration and subsequent bone remodeling of total joint replacements (TJRs). However, continuous delivery of clinically relevant particles using a viable, cost effective, quantitative animal model to simulate the scenario in humans has been a challenge for orthopedic researchers. In this study, we successfully infused blue-dyed polystyrene particles, similar in size to wear debris in humans, to the intramedullary space of the mouse femur for 4 weeks using an osmotic pump. Approximately 40% of the original particle load (85 microL) was delivered into the intramedullary space, an estimate of 3 x 10(9) particles. The visible blue dye carried by the particles confirmed the delivery. This model demonstrated that continuous infusion of particles to the murine bone-implant interface is possible. In vivo biological processes associated using wear debris particles can be studied using this new animal model.

Cell Therapy for Secondary Osteonecrosis of the Femoral Condyles Using the Cellect DBM System A Preliminary ReportJOURNAL OF ARTHROPLASTYLee, K., Goodman, S. B.2009; 24 (1): 43-48

Abstract

We describe a novel treatment of secondary osteonecrosis (ON) of the femoral condyles that is relatively simple, has low morbidity, and does not preclude the patient from other more extensive treatments in the event of failure. Three patients with extensive secondary ON of the femoral condyles were treated with decompression and debridement of the area of ON and grafting with the Cellect DBM System (Depuy Spine, Inc., Raynham, Mass), which provided a graft matrix enriched with a 3-fold to 4-fold increase in osteoprogenitor cells. At 2 years, all 3 patients had no complications and had excellent results with near-normal function and activity levels. Our preliminary results demonstrate that this technique is a viable option, at least in the short term, especially in patients with extensive, multifocal lesions.

Abstract

Macrophages play an important role in the biological response to wear particles, which can result in periprosthetic osteolysis and implant loosening. In this study, we demonstrate that polymer particles induce systemic trafficking of macrophages by non-invasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 10% (w/v) Simplex bone cement (BC) suspensions or saline (PBS). Reporter RAW264.7 macrophages which stably expressed the bioluminescent reporter gene fluc, and the fluorescence reporter gene gfp, were injected intravenously. Bioluminescence imaging was performed immediately and periodically at 2-day intervals until day 14. Compared to the non-operated contralateral femora, the bioluminescent signal of femora injected with BC suspension increased 4.7+/-1.6 and 7.8+/-2.9-fold at day 6 and 8, respectively. The same values for PBS group were 1.2+/-0.2 and 1.4+/-0.5, respectively. The increase of bioluminescence of the BC group was significantly greater than the PBS group at day 8 (p<0.05) and day 6 (p<0.1). Histological study confirmed the presence of reporter macrophages within the medullary canal of mice that received cement particles. Modulation of the signaling mechanisms that regulate systemic macrophage trafficking may provide a new strategy for mitigating the chronic inflammatory response and osteolysis associated with wear debris.

Abstract

The gold standard for bone grafting in orthopedics is autograft, however autograft has a limited supply and is associated with significant morbidity at the harvest site. One alternative, allograft bone, provides an osteoconductive scaffold, is in less limited supply, and it does not require a harvest from the patient. However, allograft lacks both osteogenic cells and osteoinductive proteins that make autograft bone so advantageous. This study provides a model to investigate strategies for augmentation of corticocancellous allograft bone discs with bone marrow-derived osteoprogenitor cells (OPCs) plus exogenous growth factors in vitro. In this model, allograft bone discs were created by cutting 1-mm thick slices from the distal femur and proximal tibia of euthanized mice. The allografts were sterilized and scanned by micro-computed tomography (microCT) to provide the pre-culture graft volume and trabecular characteristics. The discs were then seeded with OPCs harvested from murine bone marrow. The seeded grafts were placed in organ culture until harvest, after which they were re-scanned by microCT and the data compared to the corresponding pre-culture data. In addition, bone morphogenetic protein-7 (BMP-7, also know as osteogenic protein-1 or OP-1), basic fibroblast growth factor (bFGF), and OP-1 combined with bFGF were added on a daily basis to the cultures. After final microCT scanning, all grafts were sectioned and evaluated histologically after hematoxylin and eosin (H&E) staining. microCT scans of cultured allografts with cells at 3, 5, and 9 weeks showed a time-dependent, statistically significant increase in bone volume. The trabecular thickness (Tb.Th.) of grafts, from both groups that were augmented with OP-1, showed a statistically significant increase in trabecular thickness of allografts with OPCs. These data suggest that bone marrow-derived OPCs adhere to, and produce, new bone on corticocancellous allograft in vitro. When exogenous OP-1 is added to this model, an increase in the production of bone onto the corticocancellous allograft bone disc is seen. This model allows for the investigation of the effects of multiple growth factors, and other interventions, on OPCs seeded onto allograft bone in vitro.

Abstract

In vitro models are important investigative tools in understanding the biological processes involved in wear-particle-induced chronic inflammation and periprosthetic osteolysis. In the clinical scenario, particles are produced and delivered continuously over extended periods of time. Previously, we quantified the delivery of both polystyrene and polyethylene particles over 2- and 4-week time periods using osmotic pumps and collection tubes. In the present study, we used explanted mice femora in organ culture and showed that continuous intramedullary delivery of submicron-sized polymer particles using osmotic pumps is feasible. Furthermore, infusion of 2.60 x 10(11) particles per mL (intermediate concentration) of ultrahigh molecular weight polyethylene (UHMWPE) for 2 weeks and 8.06 x 10(11) particles per mL (high concentration) UHMWPE for 4 weeks both yielded significantly higher scores for bone loss when compared with controls in which only mouse serum was infused.

Abstract

The osteoconductive property of titanium (Ti) surfaces is important in orthopedic and dental implant devices. Surface modifications of Ti have been proposed to further improve osseointegration. In this study, three different materials, silicon (Si), silicon oxide (SiO(2)), and titanium oxide (TiO(2)), were used to construct nanofibers for surface coating of Ti alloy Ti-6Al-4 V (Ti alloy). MC3T3-E1 osteoprogenitor cells were seeded on nanofiber-coated discs and cultured for 42 days. DNA, alkaline phosphatase, osteocalcin, and mineralization nodules were measured using PicoGreen, enzyme-linked immunosorbent assay, and calcein blue staining to detect the attachment, proliferation, differentiation, and mineralization of MC3T3-E1 cells, respectively. The results demonstrated that the initial cell attachments on nanofiber-coated discs were significantly lower, although cell proliferation on Si and SiO(2) nanofiber-coated discs was better than on Ti alloy surfaces. TiO(2) nanofibers facilitated a higher cellular differentiation capacity than Ti alloy and tissue culture-treated polystyrene surfaces. Thus, surface modification using nanofibers of various materials can alter the attachment, proliferation, and differentiation of osteoprogenitor cells in vitro.

Abstract

Computer navigation systems generally establish the rotational alignment axis of the femoral component on the basis of user-defined anatomic landmarks. However, navigation systems can also record knee kinematics and average alignment axes established with multiple techniques. We hypothesized that establishing femoral rotational alignment with the use of kinematic techniques is more accurate and precise (repeatable) than the use of anatomic techniques and that establishing femoral rotational alignment by averaging the results of different alignment techniques is more accurate and precise than the use of a single technique.Twelve orthopaedic surgeons used three anatomic and two kinematic alignment techniques to establish femoral rotational alignment axes in a series of nine cadaver knees. The axes derived with the individual anatomic and kinematic techniques as well as the axes derived with six combination techniques--i.e., those involving averaging of the alignments established with two of the individual techniques--were compared against a reference axis established with computed tomography images of each femur.The kinematic methods were not more accurate (did not have smaller mean errors) or more precise (repeatable) than the anatomic techniques. The combination techniques were accurate (five of the six had a mean error of <5 degrees ) and significantly more precise than all but one of the single methods. The percentage of measurements with <5 degrees of error as compared with the reference epicondylar axis was 37% for the individual anatomic techniques, 30% for the individual kinematic techniques, and 58% for the combination techniques.Averaging the results of kinematic and anatomic techniques, which is possible with computer navigation systems, appears to improve the accuracy of rotational alignment of the femoral component. The number of rotational alignment outliers was reduced when combination techniques were used; however, they are still a problem and continued improvement in methods to accurately establish rotation of the femoral component in total knee arthroplasty is needed.

Abstract

Malunited intertrochanteric fracture involves anatomical changes such as medialization of the femoral canal and intramedullary remodeling and sclerosis. These changes introduce difficulties that are not ordinarily encountered with routine total hip replacement. Possible intraoperative complications include spiral femoral fracture during hip dislocation and failure to identify the femoral canal. Therefore, recognizing the anatomical changes before and during surgery is crucial. In this article, we describe specific surgical steps and techniques by which these problems may be avoided, thus minimizing potential complications.

Abstract

Wear debris affects both initial osseointegration and subsequent bone remodeling of total joint replacements (TJRs). To study the complex cascade associated with the continuous generation of particles, a robust animal model is essential. To date, an animal model that incorporates continuously delivered particles to an intramedullary orthopaedic implant has not been available. In this study, we successfully infused clinically relevant ultra high molecular weight polyethylene particles, previously isolated from joint simulator tests, to the intramedullary space of the mouse femur for 4 weeks using a subcutaneous osmotic pump. Reduction of bone volume following the 4-week infusion of UHMWPE was detected by microCT. UHMWPE particles also changed the level of Alkaline Phosphatase expression in the infused femurs. Continuous infusion of particles to the murine bone-implant interface simulated the clinical scenario of local polymer wear particle generation and delivery in humans and can be used to further study the biological processes associated with wear debris particles.

Abstract

Allografts are important alternatives to autografts for treating defects after major bone loss. Bone growth factors have both local autocrine and paracrine effects and regulate the growth, proliferation, and differentiation of osteoprogenitor cells. To study the effects of prolonged, continuous, local delivery of growth factors on bone growth, we developed a new microelectromechanical system (MEMS) drug delivery device. Bone marrow cells from mice were seeded on mouse allograft discs and cultured in osteogenic media with osteogenic protein 1 (OP-1) and/or basic fibroblast growth factor (FGF-2) delivered from MEMS devices for 6 weeks. We monitored bone formation by changes of bone volume using micro-CT scanning and release of osteocalcin using ELISA. The data suggest the MEMS devices delivered constant concentrations of OP-1 and FGF-2 to the media. Bone marrow cells grew on the allografts and increased bone volume. Addition of OP-1 increased bone formation whereas FGF-2 decreased bone formation. Local delivery of growth factors over a prolonged period modulated the differentiation of osteoprogenitor cells on allograft bone.

Abstract

Orthopedic wear debris has been implicated as a significant inhibitory factor of osteoblast differentiation. Polymethylmethacrylate (PMMA) particles have been previously shown to inhibit the differentiation of osteoprogenitors in heterogeneous murine marrow stromal cell cultures, but the effect of PMMA particles on pure osteoprogenitor populations remains unknown. In this study, we challenged murine MC3T3-E1 osteoprogenitor cells with PMMA particles during their initial differentiation in osteogenic medium. MC3T3-E1 cultures challenged with PMMA particles showed a gradual dose-dependent decrease in mineralization, cell number, and alkaline phosphatase activity at low particle doses (0.038-0.150% v/v) and complete reduction of these outcome parameters at high particle doses (> or =0.300% v/v). MC3T3-E1 cultures challenged with a high particle dose (0.300% v/v) showed no rise in these outcome parameters over time, whereas cultures challenged with a low particle dose (0.075% v/v) showed a normal or reduced rate of increase compared to controls. Osteocalcin production was not significantly affected by particles at all doses tested. MC3T3-E1 cells grown in conditioned medium from particle-treated MC3T3-E1 cultures showed a significant reduction in mineralization only. These results indicate that direct exposure of MC3T3-E1 osteoprogenitors to PMMA particles results in suppression of osteogenic proliferation and differentiation.

Current state and future of joint replacements in the hip and kneeEXPERT REVIEW OF MEDICAL DEVICESLee, K., Goodman, S. B.2008; 5 (3): 383-393

Abstract

Joint replacements of the hip and knee are among the most clinically successful operations. According to figures compiled by the American Academy of Orthopaedic Surgeons, the number of primary total hip replacements performed in the USA was 220,000 in 2003. This was 38% more than in 1996 and this number is expected to rise to 572,000 (plus another 97,000 revisions) by 2030. The number of primary total knee replacements performed in 2003 was approximately 418,000 and is expected to rise exponentially with the increasing numbers of baby boomers and the aging population. Current research focuses not only on extending implant longevity, but also on improving function to meet the increased demands of today's patients, who are likely to be younger and more active than their predecessors two decades ago. Potential advancements in arthroplasty surgery include new, more wear-resistant bearing surfaces, porous metals to enhance osseointegration and replace lost bone stock, a clearer understanding of the biological processes associated with periprosthetic osteolysis, minimally invasive surgery and computer assisted surgery. Long-term studies are needed to establish the efficacy of these new technologies.

Abstract

Aseptic loosening of implants following total joint arthroplasty remains a major cause of implant failure. Particulate debris generated primarily from wear results in inflammatory mediated periprosthetic osteolysis. Titanium is a commonly utilized metal in joint arthroplasty and titanium debris induces the production of the pro-inflammatory cytokine IL-1. To further elucidate the role of IL-1, this study examined the response of murine femora to the presence of titanium particles following implantation of an intramedullary rod in mice lacking the receptor for IL-1. We hypothesized that the inflammatory effects of wear debris on bone would be mitigated in IL-1R1 deficient mice with a resultant decrease in resorption. Femora receiving titanium particles demonstrated a marked inflammatory response in wild-type mice with increased endocortical resorption, periprosthetic membrane formation, and significant histomorphometric changes. Femora exposed to titanium particles in the knockout mice also demonstrated osteolysis with irregular deposition of trabecular bone and increased cortical porosity. The persistence of inflammation and osteolysis, despite the lack of functional IL-1R1, suggests a multi-factorial role for IL-1 in the proinflammatory cascade resulting from wear debris. This intramedullary murine model provides the ability to evaluate and quantify the proinflammatory cascade in an in vivo model approximating prosthesis failure.

Abstract

Wear particles produced from total joint replacements have been shown to stimulate a foreign body and chronic inflammatory reaction that results in periprosthetic osteolysis. Most animal models that simulate these events have used a single injection of particles, which is not representative of the clinical scenario, in which particles are continuously generated. The goal of this study was to evaluate the feasibility of an osmotic pump for the continuous delivery of clinically relevant submicron-sized particles over an extended period of time. Blue-dyed polystyrene particles and retrieved ultra-high molecular weight polyethylene (UHMWPE) particles, both suspended in mouse serum, were loaded into an Alzet mini-osmotic pump. Pumps were attached to vinyl tubing that ended with hollow titanium rods, simulating a metal implant, which was suspended in a collection vessel. The number of particles collected was evaluated over 2- and 4-week time periods. Delivery of both the polystyrene and UHMWPE particles was feasible over pump concentrations of 10(9) to 10(11) particles per pump. Furthermore, delivery efficiency of polystyrene particles decreased with increasing initial particle concentration, whereas delivery efficiency of UHMWPE particles increased slightly with increasing initial particle concentration. For UHMWPE, approximately one-third of the particles in the pump were collected at 4 weeks. This in vitro study has quantified the efficiency of a unique particle pumping system that may be used in future in vivo investigations to develop a murine model of continuous particle infusion.

Seppo Santavirta: The life and work of an orthopaedic surgeon and scientist. A tribute from his friendsJOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONSKonttinen, Y. T., Goodman, S. B., Wright, T.2008; 16: XII-XV

Abstract

The murine femoral intramedullary injection model is frequently used to examine the in vivo effects of biomaterials or cancer cells. The surgical technique includes a knee arthrotomy with patellar dislocation for intramedullary access. This study examined a less invasive surgical approach of direct injection of particles via the transpatellar tendon without patellar dislocation. By using polymethylmethacrylate injection and microCT scan, we found that, compared with the traditional technique, this new approach was more reproducible, less time consuming, and achieved identical volumes of intramedullary injections. Animal morbidity and the biomechanics of the joints were also improved as a result of the simplified procedure. Furthermore, our study suggested that an intramedullary volume in excess of 10 microL can lead to major vascular filling and so should be avoided.

Abstract

Microelectromechanical system (MEMS) technology not only provides the possibility of integration of multiple functions but also enables more precise control of dosing of therapeutic agents when the therapeutic window is very limited. Local delivery of basic fibroblast growth factor (bFGF) over a specific dose and time course is critical for mesenchymal tissue regeneration. However, bFGF is degraded quickly in vivo and difficulty of controlling the dose level impedes its effective use in angiogenesis and tissue regeneration. We constructed biodegradable micro-osmotic pumps based on MEMS technology for long-term controlled release of bFGF. The devices were constructed by micro-molding and thermal assembly of 85/15 poly(L-lactide-co-glycolide) sheets. The release of bFGF was regulated at 40 ng/day for four weeks; bioactivity was assessed by monitoring the growth of 3T3 fibroblasts. The proposed devices can be further miniaturized and used for the delivery of multiple therapeutic agents at the individual releasing schedules.

Abstract

The immune system modulates many key biological processes in humans. However, the exact role of the immune system in particle-associated periprosthetic osteolysis is controversial. Human tissue retrieval studies, in vivo and in vitro experiments suggest that the immune response to polymer particles is non-specific and macrophage-mediated. Lymphocytes may modulate this response. However direct lymphocyte activation by polymer particle-protein complexes seems unlikely. However, metallic byproducts may complex with serum proteins and lead to a Type IV, lymphocyte-mediated immune reaction. In predisposed individuals, this reaction may rarely lead to persistent painful joint effusions, necessitating debridement and excision of the bearing surfaces of the prosthesis. In these patients, retrieved periprosthetic tissues exhibit histological evidence of perivascular lymphocytic cuffing. These findings are worrisome, given the fact that increasing numbers of metal-on-metal joint implants are being implanted in younger more active individuals worldwide.

Abstract

The success of total knee arthroplasty depends in part on proper soft tissue management to achieve a stable joint. It is unknown to what degree total knee arthroplasty changes joint stability. We used a surgical navigation system to intraoperatively measure joint stability in 24 patients under going primary total knee arthroplasty to address two questions: (1) Is the total arc of varus-valgus motion after total knee arthroplasty different from the arc of varus-valgus motion in an osteoarthritic knee? (2) Does total knee arthroplasty produce equal amounts of varus/valgus motion (ie, is the knee "balanced")? We observed no difference between the total arc of varus-valgus motion before and after total knee arthroplasty; the total amount of motion was unchanged. On average, osteoarthritic knees were "unbalanced" but were "balanced" after prosthesis implantation. We found a negative correlation between the relative amount of varus/valgus motion in extension before and after prosthesis implantation in extension and a positive correlation between how well the knees were balanced after prosthesis implantation in extension and in flexion. Our data suggest immediately after implantation knees retain a greater than normal amount of varus-valgus motion, but this motion is more evenly distributed.

Abstract

In this study, we delineate the sequential expression of selected growth factors associated with bone formation in vitro. Mineralization, osteocalcin, and alkaline phosphatase (ALP-2) were measured to monitor the differentiation and maturation of osteoprogenitor cells collected from C57BL mice. Bone-related growth factors, including transforming growth factor beta (TGF-beta), fibroblast growth factor 2 (FGF-2), platelet-derived growth factor (PDGF), insulinlike growth factor (IGF)-1, vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP)-2, and BMP-7, were selected. Enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR) were used to measure growth factors at the protein and messenger ribonucleic acid (mRNA) level, respectively. The results found that ALP-2 expression increased progressively over time, whereas mineralization and osteocalcin did not become evident until culture day 14. VEGF and IGF-1 were upregulated early during proliferation. PDGF and TGF-beta mRNA expression was bimodal. FGF-2 and BMP-2 mRNAs were expressed only later in differentiation. FGF-2 mRNA signal levels were highest at day 14 and remained prominent through day 28 of culture. BMP-2 showed a similar profile as FGF-2. BMP-7 was not detectable using RT-PCR or ELISA. Strong correlations existed for the expression patterns between several early-response growth factors (VEGF, TGF-beta, and IGF-1) and were also evident for several late-response growth factors (BMP-2, PDGF, and FGF-2). Differential expression for grouped sets of growth factors occurs during the temporal acquisition of bone-specific markers as osteoprogenitor cell maturation proceeds in vitro.

Abstract

The purpose of this study was to compare the histological characteristics of an autogenous fascia lata graft alone and a fascia lata graft combined with a deltoid flap in the reconstruction of rotator cuff tears. Ten New Zealand white rabbits were divided into two groups. Infraspinatus tendon defects (1 x 1 cm) were created in each animal. Reconstruction consisted of either a fascia lata graft alone or a fascia lata graft combined with a distally based deltoid flap. At 3 months, tissue harvest and histological analysis was performed. Compared to the fascia lata graft alone, there was significantly increased remodeling activity and neovascularization in the group that included a deltoid flap. Also, there was pronounced interdigitation at the graft/flap interface in the latter group. A mutually beneficial relationship may exist when an autogenous fascial graft is combined with a functional deltoid flap for reconstructing large rotator cuff defects.

Abstract

Morselized cancellous allograft bone is frequently used in the reconstruction of bone defects in cases of revision total joint replacement, trauma, spine fusion and treated infection. However, the initial lack of viable bone cells in morselized allograft bone significantly slows the process of graft incorporation compared to autograft bone. This study examined the effects of prolonged local infusion of the growth factors bone morphogenic protein-7 (BMP-7 or OP-1) and fibroblast growth factor-2 (FGF-2 or basic FGF) in the process of allograft incorporation using a rabbit tibial chamber model. New bone formation was evaluated by two indices, the activity of alkaline phosphatase and the level of birefringence. The markers of osteoclast-like cells were also measured. Without the infusion of the growth factors, lower levels of new bone formation were observed in the allograft group, compared to the autograft group. Infusion of growth factors FGF-2 and OP-1, singly or in combination, for 4 weeks, diminished this difference. The numbers of osteoclast-like cells were much higher in the allograft group before the growth factors were delivered. The infusion of FGF, singly, diminished this difference. However, the infusion of OP-1 or the combination of FGF and OP-1 did not decrease the number of osteoclast-like cells to a level comparable to autograft only. Local infusion of growth factors appears to be a useful adjunct to promote the incorporation of allograft bone in vivo.

Abstract

Medications taken for the treatment of arthritis and psychotropic and epileptic disorders, as well as anticoagulants, antacids, bisphosphonates, corticosteroids, and antineoplastic drugs, can profoundly affect bone metabolism. In some scenarios (eg, osteoporosis), these effects are intended; in others (eg, rickets, osteomalacia secondary to antiepileptic drugs), potentially adverse side effects of medications on bone may occur. Nonsteroidal anti-inflammatory drugs appear to delay fracture healing and bone ingrowth, although these effects are reversible. Disease-modifying antirheumatic drugs do not appear to affect bone metabolism adversely when taken in the low dosages currently prescribed. Bisphosphonates are useful in restoring bone mass in cases of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, and neoplastic conditions with bone loss and hypercalcemia. Corticosteroids and cancer chemotherapeutic agents generally affect bone adversely and increase fracture risk.

Dissociation of the femoral head and trunion after constrained conversion total hip arthroplasty for poliomyelitisJOURNAL OF ARTHROPLASTYSpinnickie, A., Goodman, S. B.2007; 22 (4): 634-637

Abstract

A conversion total hip arthroplasty using a 58-mm cementless shell and screws and constrained acetabular liner was performed in a 71-year-old patient with a nonunion of an intertrochanteric fracture and poliomyelitis with flail extremities. Preoperatively, the fractured lower extremity was painful and normally used by the patient for pivot transfers from his wheelchair. Five months postoperatively, the patient sustained complete dissociation of the trunion and femoral head, which was still located within the constrained liner. All other components were well fixated and properly positioned. The hip was revised successfully with a 40-mm femoral head and a nonconstrained liner with a 15 degrees elevated lip placed posterosuperiorly.

Abstract

The effects of an oral p38 mitogen-activated protein kinase (MAPK) inhibitor and polyethylene particles separately and together on tissue differentiation in the bone harvest chamber (BHC) in rabbits over a 3-week treatment period were investigated. The harvested tissue was analyzed histomorphometrically for markers of bone formation (percentage of bone area), osteoblasts (alkaline phosphatase staining), and osteoclasts (CD51, the alpha chain of the vitronectin receptor). Polyethylene particles decreased the percentage of bone ingrowth and staining for alkaline phosphatase. The p38 MAPK inhibitor alone decreased alkaline phosphatase staining. When the oral p38 MAPK inhibitor was given and the chamber contained polyethylene particles, there was a suppression of bone ingrowth and alkaline phosphatase staining. In contrast to oral non-steroidal anti-inflammatory drugs (NSAIDs) and local Interleukin-1 receptor antagonist (IL-1ra) administration, the oral p38 MAPK inhibitor alone did not suppress bone formation when given during the initial phase of tissue differentiation. Particle-induced inflammation and the foreign body reaction were not curtailed when the p38 MAPK inhibitor was given simultaneously with particles. Additional experiments are needed to establish the efficacy of p38 MAPK inhibitor administration on mitigating an established inflammatory and foreign body reaction that parallels the clinical situation more closely.

Abstract

Periprosthetic bone loss induced by implant wear debris may be a combined effect of osteolysis and reduced bone formation resulting from particle-induced suppression of osteoprogenitor differentiation. This study investigated the time-dependent effects of polymethylmethacrylate (PMMA) particles on the osteogenic capability of bone marrow osteoprogenitor cells during the early phase of differentiation. Murine bone marrow cells were challenged with PMMA particles (0.30% v/v) on the first day of growth in osteogenic medium. Particles were removed from culture after 1, 3, and 5 days, respectively, after which cell growth in osteogenic medium was continued until the 15th day. Bone marrow osteoprogenitor cells exposed to particles during the first 5 days of differentiation showed complete, irreversible inhibition of proliferation, alkaline phosphatase expression, and mineralization. Osteoprogenitors exposed to particles for more than 5 days showed the same degree of inhibition, while those exposed to particles for less than 5 days showed a diminished inhibitory response. Conditioned medium from particle-treated cells did not suppress osteogenic development, demonstrating that suppression of osteogenesis was not due to secreted inhibitory factors. This study has shown that the early phase of osteoprogenitor differentiation is a crucial time period during which exposure to PMMA particles causes irreversible inhibition of osteogenesis.

Abstract

A new generation of surgical tools, known as surgical navigation systems, has been developed to help surgeons install implants more accurately and reproducibly. Navigation systems also record quantitative information such as joint range of motion, laxity, and kinematics intra-operatively. This article reviews the history of surgical navigation for total knee arthroplasty, the biomechanical principles associated with this technology, and the related clinical research studies. We describe how navigation has the potential to address three main challenges for total knee arthroplasty: ensuring excellent and consistent outcomes, treating younger and more physically active patients, and enabling less invasive surgery.

Abstract

Excessive polyethylene wear particles from joint replacements may lead to periprosthetic osteolysis and loosening. Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease fracture healing and bone ingrowth. We hypothesized that continuous local infusion of OP-1 (BMP-7) would increase local bone formation in the presence of two different adverse stimuli, polyethylene particles, and an oral NSAID. The Drug Test Chamber (DTC) was implanted in the proximal tibia of mature rabbits. The tissue growing into the chamber was exposed to OP-1 solution (110 ng/day), which was infused via an osmotic pump. Infusion of OP-1 alone for 6 weeks enhanced local bone formation in the chamber by 80% (p < 0.05) over infusion of carrier alone. In the presence of polyethylene particles, infusion of OP-1 increased local bone formation by 38% (p < 0.05) over treatment with particles and carrier. Oral administration of NSAID reduced local bone formation by 58% (p < 0.05); this suppressive effect caused by NSAIDS was completely reversed by the infusion of OP-1 (p < 0.05). These findings underline a potential role for local treatment with OP-1 to increase bone formation in the presence of potentially adverse stimuli such as polyethylene wear particles or NSAID use.

Abstract

Wear particles from total joint arthroplasties are constantly being generated throughout the lifetime of an implant. Since mesenchymal stem cells and osteoprogenitors from the bone marrow are the precursors of osteoblasts, the reaction of these cells to orthopaedic wear particles is critical to both initial osseointegration of implants and ongoing regeneration of the periprosthetic bed. Particles less than 5 microm can undergo phagocytosis by mature osteoblasts, with potential adverse effects on cellular viability, proliferation and function. The specific effects are dependent on particle composition and dose. Metal and polymer particles in non-toxic doses stimulate pro-inflammatory factor release more than ceramic particles of a similar size. The released factors inhibit markers of bone formation and are capable of stimulating osteoclast-mediated bone resorption. Mesenchymal stem cells and osteoprogenitors are also profoundly affected by wear particles. Titanium and polymethylmethacrylate particles inhibit bone cell viability and proliferation, and downregulate markers of bone formation in a dose- and time-dependent manner. Future studies should delineate the molecular mechanisms by which particles adversely affect mesenchymal stems cells and the bone cell lineage and provide strategies to modulate these effects.

Abstract

Although various techniques are advocated to establish tibial rotational alignment during total knee arthroplasty, it is unknown which is most repeatable. We evaluated the precision and accuracy of five tibial rotational alignment techniques to determine whether computer-assisted navigation systems can reduce variability of tibial component rotational alignment when compared to traditional instrumentation. Eleven orthopaedic surgeons used four computer-assisted techniques that required identification of anatomical landmarks and one that used traditional extramedullary instrumentation to establish tibial rotational alignment axes on 10 cadaver legs. Two computer-assisted techniques (axes between the most medial and lateral border of the tibial plateau, and between the posterior cruciate ligament [PCL] and the anterior tibial crest) and the traditional technique were least variable, with standard deviations of 9.9 degrees, 10.8 degrees, and 12.1 degrees, respectively. Computer-assisted techniques referencing the tibial tubercle (axes between the PCL and the medial border or medial 1/3 of the tubercle) were most variable, with standard deviations of 27.4 degrees and 28.1 degrees. The axis between the medial border of the tibial tubercle and the PCL was internally rotated compared to the other techniques. None of the techniques consistently established tibial rotational alignment, and navigation systems that establish rotational alignment by identifying anatomic landmarks were not more reliable than traditional instrumentation.

Abstract

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Abstract

This study tested the hypothesis that physiologic tendon loading modulates the fibrous connective tissue phenotype in undifferentiated skeletal cells. Type I collagen sponges containing human bone marrow stromal cells (MSCs) were implanted into the midsubstance of excised sheep patellar tendons. An ex vivo loading system was designed to cyclically stretch each tendon from 0 to 5% at 1.0 Hz. The MSC-sponge constructs were implanted into 2 tendon sites: the first site subjected to tension only and a second site located at an artificially created wrap-around region in which an additional compressive stress was generated transverse to the longitudinal axis of the tendon. The induced contact pressure at the wraparound site was 0.55 +/- 0.12 MPa, as quantified by pressure-sensitive film. An MSC-sponge construct was maintained free swelling in the same bath as an unloaded control. After 2 h of tendon stretching, the MSC-sponge constructs were harvested and real-time PCR was used to quantify Fos, Sox9, Cbfa1 (Runx2), and scleraxis mRNA expression as markers of skeletal differentiation. Two hours of mechanical loading distinctly altered MSC differentiation in the wrap-around region and the tensile-only region, as evidenced by differences in Fos and Sox9 mRNA expression. Expression of Fos mRNA was 13 and 52 times higher in the tensile-only and wrap-around regions, respectively, compared to the free-swelling controls. Expression of Sox9 mRNA was significantly higher (2.5-3 times) in MSCs from the wraparound region compared to those from the tensile-only region or in free-swelling controls. In contrast, expression levels for Cbfa1 did not differ among constructs. Scleraxis mRNA was not detected in any construct. This study demonstrates that the physiologic mechanical environment in the wrap-around regions of tendons provides stimuli for upregulating early response genes and transcription factors associated with chondrogenic differentiation. These differentiation responses begin within as little as 2 h after the onset of mechanical stimulation and may be the basis for the formation of fibrocartilage that is typically found in the wrap-around region of mature tendons in vivo.

Abstract

This study examined effects of varying magnitudes of intermittent hydrostatic pressure (IHP) applied for different times on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. hMSCs were exposed to 0.1, 1, and 10 MPa of IHP at a frequency of 1 Hz for 4 h/day for 3, 7, and 14 days in the presence of transforming growth factor (TGF-beta3). Chondrogenesis was characterized by gene expression, macromolecule production, and extracellular matrix deposition. Exposure of hMSCs to 0.1 MPa of IHP increased SOX9 and aggrecan mRNA expression by 2.2- and 5.6-fold, respectively, whereas type II collagen mRNA expression responded maximally at 10 MPa. Production of sulfated glycosaminoglycan responded to IHP of 1 MPa and 10 MPa, whereas collagen levels increased only at 10 MPa. Morphologically, matrix condensation occurred with increased IHP, concomitant with collagen expression. This study demonstrated that different levels of IHP differentially modulate hMSC chondrogenesis in the presence of TGF-beta3. The data suggest that tissue engineering of articular cartilage through application or recruitment of hMSCs can be facilitated by mechanical stimulation.

Abstract

Total knee arthroplasty is a successful procedure to treat pain and functional disability due to osteoarthritis. However, precisely how a total knee arthroplasty changes the kinematics of an osteoarthritic knee is unknown. We used a surgical navigation system to measure normal passive kinematics from 7 embalmed cadaver lower extremities and in vivo intraoperative passive kinematics on 17 patients undergoing primary total knee arthroplasty to address two questions: How do the kinematics of knees with advanced osteoarthritis differ from normal knees?; and, Does posterior substituting total knee arthroplasty restore kinematics towards normal? Osteoarthritic knees displayed a decreased screw-home motion and abnormal varus/valgus rotations between 10 degrees and 90 degrees of knee flexion when compared to normal knees. The anterior-posterior motion of the femur in osteoarthritic knees was not different than in normal knees. Following total knee arthroplasty, we found abnormal varus/valgus rotations in early flexion, a reduced screw-home motion when compared to the osteoarthritic knees, and an abnormal anterior translation of the femur during the first 60 degrees of flexion. Posterior substituting total knee arthroplasty does not appear to restore normal passive varus/valgus rotations or the screw motion and introduces an abnormal anterior translation of the femur during intraoperative evaluation.

Abstract

The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been implicated in periprosthetic osteolysis and subsequent aseptic loosening of implants following total hip arthroplasty (THA). The goal of this study was to investigate whether increased VEGF at the bone-implant interface is secondary to a greater number of VEGF-producing cells or to increased VEGF production by individual cells. Real time polymerase chain reaction (RT-PCR) techniques were used to assess the expression of VEGF mRNA (isoforms 121, 165, 189) in periprosthetic tissues from revision THAs. Immunofluorescence was used to determine both differences in overall cellularity and in VEGF-producing cell type (macrophages, fibroblasts, endothelial cells) between patients with periprosthetic osteolysis (OL) and a control group undergoing primary THA for osteoarthritis (OA). Quantitative analysis of VEGF release in periprosthetic membranes via RT-PCR demonstrated no significant difference in the per-cell mRNA production of VEGF isoforms 121 165, or 189 between OL and OA patient groups. Immunofluorescence showed both higher cellularity and higher overall VEGF expression in the OL group. Immunofluorescence also showed a significant increase in macrophages in the OL group, but no significant difference in the proportion of fibroblasts or endothelial cells between the OL and OA groups. Co-localization of CD68+ and CD11b+ macrophage fluorescent signals with VEGF signal was greater in the OL group than in the OA group. Our results demonstrate that increased VEGF in OL periprosthetic tissue compared to OA synovium is correlated to increased numbers of VEGF-producing CD68+ and CD11b+ macrophages. Impact statement: Aseptic loosening, caused in large part by OL, remains the major cause of failed THAs leading to revision surgery. At the bone-implant interface, we found increased numbers of macrophages-cellular mediators of OL-and increased VEGF expression. VEGF may be a possible target for therapeutic intervention in mitigating OL.

Abstract

Aseptic implant loosening of total joint replacements often results from particle-mediated bone loss, which may be a combined effect of osteolysis and suppressed bone formation. Bone regeneration in the prosthetic bed depends on the activity of osteoblasts and their differentiation from osteoprogenitors in the bone marrow. This study investigated the effects of polymethylmethacrylate (PMMA) particles on the ability of bone marrow osteoprogenitors to differentiate into osteoblasts in vitro. Murine bone marrow cells challenged with PMMA particles on the first day of differentiation in osteogenic medium showed a dose-dependent decrease in osteoprogenitor proliferation, alkaline phosphatase expression, and mineralization. Undifferentiated bone marrow cells pretreated with PMMA particles in nonosteogenic medium for 5 days also showed a dose-dependent loss in osteogenic potential, which was sustained throughout subsequent growth in particle-free, osteogenic medium. Bone marrow cells challenged with PMMA particles after the fifth day of differentiation in osteogenic medium showed significant reductions in cellular proliferation, but not alkaline phosphatase expression and mineralization, indicating that bone marrow cells were most sensitive to particle treatment during the first 5 days of differentiation. This study demonstrated that PMMA particles inhibit osteoblastic differentiation of bone marrow osteoprogenitor cells, which may contribute to periprosthetic bone loss and implant failure.

Abstract

This study examined the effects of intermittent hydrostatic pressure (IHP) and transforming growth factor-beta 3 on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. Chondrogenic gene expression was determined by quantifying mRNA signal levels for SOX9, a transcription factor critical for cartilage development and the cartilage matrix proteins, aggrecan and type II collagen. Extracellular matrix production was determined by weight and histology. IHP was applied to hMSCs in pellet culture at a level of 10 MPa and a frequency of 1 Hz for 4 h per day for periods of 3, 7, and 14 days. hMSCs responded to addition of TGF-beta 3 (10 ng/mL) with a greater than 10-fold increase (p < 0.01) in mRNA levels for each, SOX9, type II collagen, and aggrecan during a 14-day culture period. Applying IHP in the presence of TGF-beta 3 further increased the mRNA levels for these proteins by 1.9-, 3.3-, and 1.6-fold, respectively, by day 14. Chondrogenic mRNA levels were increased with just exposure to IHP. Extracellular matrix deposition of type II collagen and aggrecan increased in the pellets as a function of treatment conditions and time of culture. This study demonstrated adjunctive effects of IHP on TGF-beta 3-induced chondrogenesis and suggests that mechanical loading can facilitate articular cartilage tissue engineering.

Abstract

We report the outcome of a prospective consecutive series of 52 primary total hip arthroplasties using the miniature porous-coated Anatomic Medullary Locking stem in patients with small anatomic proportions because of hip dysplasia or juvenile chronic arthritis. The mean age of the patients at the time of surgery was 28.7 years (range 14-56 years). The average body weight and height of the patients were 51.8 kg (range 38.5-78.3 kg) and 157.1 cm (range 142.2-183 cm), respectively. The stem was cementless in 40 hips and cemented in 12 hips because of poor bone stock. A cementless acetabular cup with screw was used in all hips. The average followup was 7.1 years (range, 3-15.6 years). The Harris hip scores improved from an average of 31.2 points (range, 3.1-68.8 points)preoperatively to 82.8 points (range, 61.1-96.6 points) at latest followup. Three of 12 (25%) cemented and two of 40 (5%) cementless stem were revised. Four of seven 42-44-mm cups were revised. The miniature Anatomic Medullary Locking cementless femoral stem provides a satisfactory outcome in patients with small anatomic proportions. However, wear and osteolysis with the use of a small cementless polyethylene liner remain challenges.

Abstract

Wear particles generated following total joint arthroplasty interact with cells at the periprosthetic margin and induce an inflammatory response that contributes to osteolysis, aseptic loosening, and implant failure. This study examined the long-term effects of particles from two commonly implanted materials, titanium (Ti) and polymethylmethacrylate (PMMA), on cell viability and metabolism over a 21-day time course, using the human osteoblast-like cell line MG-63. Addition of particles was not associated with increased cell death or nitric oxide production at the particle concentration chosen. Collagen production was increased with exposure to titanium particles, whereas alkaline phosphatase and osteocalcin expression remained unchanged following exposure to both types of particles. The data show that titanium but not PMMA particles shifts bone cell metabolism to preferentially produce fibrous tissue rather than bone.

Abstract

Revision total hip arthroplasty (THA) in patients with juvenile chronic arthritis (JCA) is complicated by the young age of the patient, poor bone stock and small physical proportions. We report the complications and outcome of a prospective series of 17 revision THAs in Charnley class C JCA patients.15 acetabular components and 10 femoral components were revised. 13 cementless cups, 2 reconstruction/roof rings and cemented cups, and 4 cemented and 6 cementless femoral stems were implanted. 2 proximal femoral allografts and 1 strut allograft were used. Age at revision was 32 (21-53) years. Follow-up averaged 7 (4-12) years.2 patients with cemented femoral stems developed loosening, osteolysis and fracture. Both were successfully revised to long-stem cementless implants with strut/proximal femoral allografts. 1 loose, worn cementless cup with osteolysis was revised. 1 patient with a peri-operative infection and late acetabular fracture had a loose, non-revised cementless cup. 1 case of sciatic nerve palsy occurred after revision using a reconstruction ring. 1 late infection necessitated resection arthroplasty. Harris hip scores improved from 53 (34-85) to 76 (47-96).Revision THA in JCA has a substantial complication rate, even in experienced hands. The problem of obtaining long-term stable fixation, osteolysis, and replenishment of lost bone stock are major difficulties.

Abstract

Several reference axes are used to establish femoral rotational alignment during total knee arthroplasty, but debate continues with regard to which axis is most accurately and easily identified during surgery. Computer-assisted navigation systems have been developed in an attempt to more accurately and consistently align implants during total knee arthroplasty, but it is unknown if navigation systems can improve the accuracy of femoral rotational alignment as compared with that achieved with more traditional techniques involving mechanical guides. The purposes of the present study were to characterize the variability associated with femoral rotational alignment techniques and to determine whether the use of a computer-assisted surgical navigation system reduced this variability.Eleven orthopaedic surgeons used five alignment techniques (including one computer-assisted technique and four traditional techniques) to establish femoral rotational alignment axes on ten cadaveric specimens, and the orientation of these axes was recorded with use of a navigation system. These derived axes were compared against a reference transepicondylar axis on each femur that was established after complete dissection of all soft tissues.There was no difference between the mean errors of all five techniques (p > 0.11). Only 17% of the knees were rotated <5 degrees from the reference transepicondylar axis, with alignment errors ranging from 13 degrees of internal rotation to 16 degrees of external rotation. There were significant differences among the surgeons with regard to their ability to accurately establish femoral rotational alignment axes (p < 0.001).All techniques resulted in highly variable rotational alignment, with no technique being superior. This variability was primarily due to the particular surgeon who was performing the alignment procedure. A navigation system that relies on directly digitizing the femoral epicondyles to establish an alignment axis did not provide a more reliable means of establishing femoral rotational alignment than traditional techniques did.

Abstract

Accurate alignment of the mechanical axis of the limb is important to the success of a total knee arthroplasty. Although computer-assisted navigation systems can align implants more accurately than traditional mechanical guides, the ideal technique to determine the distal end point of the mechanical axis, the center of the ankle, is unknown. In this study, we evaluated the accuracy, precision, objectivity, and speed of five anatomic methods and two kinematic methods for estimating the ankle center in 11 healthy subjects. Magnetic resonance images were used to characterize the shape of the ankle and establish the true ankle center. The most accurate and precise anatomic method was establishing the midpoint of the most medial and most lateral aspects of the malleoli (4.5 +/- 4.1 mm lateral error; 2.7 +/- 4.5 mm posterior error). A biaxial model of the ankle (2.0 +/- 6.4 mm medial error; 0.3 +/- 7.6 mm anterior error) was the most accurate kinematic method. Establishing the midpoint of the most medial and most lateral aspects of the malleoli was an accurate, precise, objective, and fast method for establishing the center of the ankle.

Abstract

We examined the effects of ultra-high molecular weight polyethylene (UHMWPE) particles on mononuclear cell proinflammatory gene expression in a novel murine model. We hypothesized that mononuclear cell gene transcription of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1) would be upregulated by the addition of polyethylene particles in this murine intramedullary rod model.The model involved a stainless steel Kirschner wire inserted retrograde with a line-to-line fit in bilateral femora of C57bl/6 mice. Additionally, the right femora were injected with 3 x 10(9) UHMWPE particles. Mononuclear marrow cells were isolated by bone marrow aspiration and Ficoll-Paque centrifugation at 2, 4 and 10 weeks post-surgery. Total RNA was isolated and real-time RT-PCR was performed to quantify gene expression. Histological specimens of explanted femora were also analyzed to track the changes in periprosthetic tissue.UHMWPE particles stimulated gene transcription in mononuclear cells when examined at 2, 4 and 10 weeks post-surgery, compared to the rod-only group. Relative levels of IL-1beta and MCP-1 mRNA increased in a linear fashion over the 10-week time-course. IL-6 mRNA showed increased expression which peaked at 4 weeks. TNF-alpha mRNA expression was variable and reached a minimum at 4 weeks. The addition of UHMWPE particles stimulated ingress of macrophages and multinuclear cells of macrophage origin to the bone-implant interface.In this model, a single bolus of UHMWPE particles had a long-term effect on gene transcription in mononuclear cells which perpetuated a chronic inflammatory state. This murine model of intramedullary particle-induced inflammation simulates periprosthetic events associated with implant wear in humans, and may contribute to a more mechanistic understanding of wear-debris associated prosthesis failure.

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that has been implicated in wear-debris associated total joint replacement failure. We hypothesized that the absence of the IL-1 type-1 receptor would mitigate the inflammatory response to titanium particles and decrease periprosthetic inflammatory tissue in a murine intramedullary rod model.An intramedullary rod with and without commercially pure titanium particles was placed in the femora of 24 wild type mice (WT) and 24 mice lacking a functional type-1 receptor to IL-1. Femora were analyzed histologically and by ELISA of organ culture explant supernatants.The presence of titanium particles in WT mice stimulated increased expression of interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1) relative to rod only controls. In contrast, IL-6 and MCP-1 expression were diminished in IL-1r1-KO mice exposed to titanium particles. Additionally, the formation of a periprosthetic fibro-inflammatory membrane in IL-1r1-KO mice was blunted at 2 weeks when compared to that in wild-type mice. Inflammatory changes and the quality of periprosthetic bone of IL-1r1-KO mice was similar to WT mice in response to titanium particles.These results implicate IL-1 as an important modulator in the local inflammatory response to intramedullary titanium particles. MCP-1 appears to be significantly modulated in IL-1r1-KO mice in response to titanium particles. This may be responsible, in part, for the diminished periprosthetic membrane observed in IL-1r1-KO mice at 2 weeks. Expansion of this murine model of intramedullary particle-induced inflammation to other gene targets may contribute to a more mechanistic understanding of wear-debris associated prosthesis failure.

Abstract

The optimal techniques and implants for total knee arthroplasty in patients with juvenile rheumatoid arthritis are controversial. We report the functional outcomes and complications of a series of 17 cemented total knee arthroplasties done by one surgeon during a 10-year period in which off-the-shelf implants were used, the posterior cruciate ligament was excised, and a lateral retinacular release was done. Preoperatively, all knees had severe loss of normal joint space and osteopenia on 3-foot, standing AP radiographs, lateral radiographs, and patellofemoral views. The patients were evaluated after a mean followup of 74 months (range, 36-116 months). The Knee Society scores improved from a mean of 38.9 +/- 23.9 points (range, 10-81 points) preoperatively to 81.9 +/- 16.6 points (range, 39-99 points) postoperatively. Range of motion showed significant improvement in all patients at the most recent followup. Ambulation scores improved significantly; nine of 10 patients (15 knees) were ambulatory after surgery. Complications included two transient regional pain syndromes and one patellofemoral subluxation requiring realignment. Cemented total knee arthroplasty with off-the-shelf implants, excision of the posterior cruciate ligament, and lateral retinacular release in patients with juvenile rheumatoid arthritis can provide substantial improvement in pain, deformity, ambulation, and function.Therapeutic study, Level IV (case series--no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.

Abstract

The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.

Abstract

Total joint replacements of the hip and knee are generally highly successful, with satisfactory longevity and clinical results. Using modern biocompatible materials, optimal component design, and meticulous surgical technique, survivorship of cemented or cementless joint replacements is approximately 15 years with more than a 90% probability. The host's biologic response is critical to implant longevity. Particulate disease refers to the host's adverse biologic response to wear debris and byproducts generated from the prosthesis. Initially, emphasis was placed on particulate polymethylmethacrylate (cement disease), but more recently polyethylene wear debris has been underscored. Debris from several materials in sufficient quantities and physicochemical forms, however, can generate an inflammatory cascade resulting in periprosthetic bone destruction (osteolysis), jeopardizing long-term success of the implant.

Abstract

In general, longer operative times and in some cases increased blood requirements can be expected with TKA in patients with juvenile rheumatoid arthritis. Complications also are more frequent. Pain relief is usually good to excellent, and function and deformity are significantly improved. Range of motion after TKA for juvenile rheumatoid arthritis is usually less than that obtained in osteoarthritis, but still allows for dramatic improvements in performing activities of daily living (Figure 3).

Abstract

Wear and periprosthetic osteolysis of total joint replacements continue to be the most important problems in arthroplasty surgery. Despite the introduction of improved technologies including alternative bearing surfaces for TJRs, wear is inevitable because of relative movement at different interfaces and processes such as electrolysis and material degradation. Worn, clinically failing implants need to be followed closely and revised when appropriate. However, early wear and minor osteolysis do not result necessarily in progressive failure of the prosthesis. Indeed such cases may be followed up clinically and radiographically to establish the functional and biologic sequelae of wear and the timeline of these events. This scenario provides an opportunity to modulate the adverse biologic reaction associated with wear particles that includes chronic inflammation, the foreign body response, and periprosthetic bone destruction. Currently, immunological events associated with wear particles are becoming understood more clearly. Strategies to mitigate adverse processes associated with wear debris include local or systemic administration of immune modulators, signaling molecules, anti-inflammatory agents and growth factors, and altering osteoclast function. Ultimately, prevention of accelerated wear and periprosthetic osteolysis will be achieved with improved bearing surfaces and prosthetic designs.

Abstract

Traditional trochanteric sliding osteotomy preserves the lateral aspect of the greater trochanter, the abductors, and vastus lateralis in continuity. Our modification uses a lateral approach to the hip and osteotomy immediately anterior to the insertion of the posterior capsule and external rotators onto the greater trochanter. The osteotomy and attached abductors and vastus lateralis are translated anteriorly, leaving the posterior capsule and external rotators attached to the proximal femur. This surgical approach preserves the posterior soft-tissue stabilizing structures that resist posterior dislocation of the hip. In a retrospective review of 2 consecutive 2-year series of acetabular component revisions only between 1997 and 2001, 4 of 27 acetabular revisions using a traditional trochanteric slide subsequently dislocated; only 1 of 30 subsequent cases using a modified sliding trochanteric osteotomy dislocated. Modified sliding trochanteric osteotomy facilitated surgical exposure and produced a trend toward a lower dislocation rate that did not reach statistical significance with the small numbers of patients available.

Abstract

Wear debris from total joint replacement prostheses is implicated in periprosthetic osteolysis and implant loosening. The pathophysiology of this biological process remains unclear. Animal models of particle-induced osteolysis have proven useful in the study of specific tissue responses to wear debris. However, existing in vivo murine models of particle-mediated inflammation do not permit analysis of cortical bone degradation. This study describes a murine model of particle disease using an intramedullary rod in the mouse femur to parallel the clinical situation. The model consists of placing a 10-mm-long Kirschner wire retrograde in both femurs of C57b1/6 male mice via a medial parapatellar arthrotomy. Phagocytosable titanium particles were also implanted unilaterally to replicate generation of wear debris. Mice were sacrificed at 2, 10, and 26 weeks and whole femurs were cultured for 72 h. Levels of interleukin-6, monocyte chemotactic protein-1, and macrophage colony stimulating factor were assayed by ELISA. Transverse histological sections, at the level of the implant, were taken and stained with hematoxylin and eosin (H&E). Results demonstrated increased expression of proinflammatory mediators at 2 weeks in femora with rod and particles compared to femora with rods alone. Destruction of the endosteum was evident at 2, 10, and 26 weeks in the femora with titanium. This novel murine model of particle-induced intramedullary inflammation may facilitate cost-effective genetic studies and offers investigators a simple, clinically relevant intramedullary model to readily examine the pathogenesis of particle-mediated periprosthetic osteolysis.

Abstract

This study tested the hypothesis that intermittent hydrostatic pressure applied to human osteoarthritic chondrocytes modulates matrix metalloproteinase and pro-inflammatory mediator release in vitro.Human osteoarthritic articular chondrocytes were isolated and cultured as primary high-density monolayers. For testing, chondrocyte cultures were transferred to serum-free medium and maintained without loading or with exposure to intermittent hydrostatic pressure (IHP) at 10 MPa at a frequency of 1 Hz for periods of 6, 12 and 24 h. Levels of matrix metalloproteinase-2, -9 (MMP-2, -9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and the pro-inflammatory mediators, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), released into the culture medium were assessed by ELISA. Matrix metalloproteinase activity was confirmed by zymographic analysis.In the absence of IHP, levels of MMP-2, TIMP-1, IL-6, and MCP-1 in the chondrocyte culture medium increased in a time-dependent manner. Application of IHP decreased MMP-2 levels at all time periods tested, relative to unloaded control cultures maintained for the same time periods. Although 84/82 kDa bands were faintly detectable by zymography, MMP-9 levels were not quantifiable in medium from loaded or unloaded cultures by ELISA. TIMP-1 levels were not altered in response to IHP at any time period tested. IL-6 and MCP-1 levels decreased in cultures exposed to IHP at 12 and 24 h, relative to unloaded control cultures maintained for the same time periods.IHP decreased release of MMP-2, IL-6 and MCP-1 by osteoarthritic chondrocytes in vitro suggesting that pressure influences cartilage stability by modulating chondrocyte expression of these degradative and pro-inflammatory proteins in vivo.

Abstract

The study objective was to determine the tissue response to polyethylene and/or titanium particles and the role that these play in peri-prosthetic osteolysis in a rabbit model of implant failure. Twenty-two mature rabbits were used. Unilateral tibial arthroplasty was performed on all of them. The test animals received implants that were intentionally rotationally unstable with reference to the host tibia in order to create a model of failure. The test rabbits were divided into three groups. Group 1 consisted of seven rabbits in which only the carrier was implanted. Group 2 consisted of seven rabbits that received only polyethylene particles suspended in the carrier. Group 3 consisted of eight rabbits that received a mixture of polyethylene and titanium alloy particles suspended in the carrier. The rabbits were sacrificed at 6 months post surgery. The entire knee, together with the immediately surrounding soft tissue, was retrieved. The position of the implant in each rabbit was assessed with reference to its alignment to the tibia. The number of inflammatory, foreign-body reactive cells, the presence of neovascularization, edema, and necrosis in the periprosthetic zones were recorded and assessed in a qualitative and semiquantitative manner. Quantitative histomorphometry was used to determine the proportion of implant surface that interfaced with osseous or fibrous tissue. Also assessed was the thickness and maturity of the fibrous tissue and the endosteal remodeling activity in the peri-implant bone counting both osteoclastic and osteoblastic activity. The results showed that implanted particles and misalignment of the implants combined to produce peri-prosthetic bone resorption. Bone resorption was found to be proportional to the degree of misalignment. The animals that received combined polyethylene/titanium particles had a greater degree of foreign-body and inflammatory response with osteolysis than the other groups. The combination of bio-material particles (polyethylene and titanium alloy) produced a greater degree of bone resorption than the single biomaterial particles (polyethylene). The amount of bone resorption surrounding the implant was directly proportional to the degree of misalignment of the implant.

Abstract

The objective of this study was to quantify the effect of collar geometry on stress transfer and micromotion in idealized models of a cementless implant having an intramedullary stem.Intramedullary stems exist on several types of orthopaedic implants, including the femoral component of hip arthroplasties and segmental replacements used in the surgical treatment of a tumor or trauma in the diaphysis of a long bone.Using three-dimensional finite element analysis, we compared four idealized, straight-stemmed, axisymmetric prostheses: flat-collared (0 degrees), conical-collared (30 degrees and 60 degrees), and collarless tapered (80 degrees). We simulated axial and non-axial (20 degrees oblique) loads as well as non-ingrown and ingrown interface conditions.Without bone ingrowth, stress transfer to bone adjacent to the collar increased with collar angle. Micromotion at the distal stem increased moderately with collar angle from 0 degrees through 60 degrees, then increased markedly from 60 degrees to 80 degrees. With simulated bony ingrowth, the effect of the collar was greatly reduced.The results of this study suggest that the selection of collar angle represents a tradeoff between initial stress transfer and micromotion. Stems with conical collar angles in the range of 30-60 degrees can provide increased stress transfer compared to a flat collar design and reduced micromotion compared to a collarless tapered design.

Abstract

The complications, management, and outcome of a consecutive series of 61 ilioischial reconstruction rings performed by 1 surgeon over a 15-year period are reported. Structural corticocancellous allografts were used in 48 cases. Twenty-seven cases had no complications, 9 had medical complications, and 5 had complications related to femoral revision. Other complications included 4 sciatic and 2 peroneal nerve palsies, 4 rings that lost fixation, 1 possibly loose ring, 3 fractured flanges, 3 loose cups, 7 dislocations, and 3 deep infections. Success, defined as a stable reconstruction with no further acetabular revision and bone graft incorporation, was 76%. We recommend a constrained acetabular liner to avoid dislocation in selected cases, slotting the ischial flange into bone for further ring stability and protection of the sciatic nerve.

Abstract

Although interleukin-1 (IL-1) has been implicated in the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are largely unknown. Recently, a cytokine-driven, stromal cell-free mouse osteoclastogenesis model was established. A combination of macrophage colony stimulating factor (M-CSF) and receptor activator of NFkappaB ligand (RANKL) was proven to be sufficient in inducing differentiation of bone marrow hematopoietic precursor cells to bone-resorbing osteoclasts in the absence of stromal cells or osteoblasts. This study utilizes this model to examine the impact of human IL-1beta on in vitro osteoclastogenesis of bone marrow progenitor cells. We found that osteoclast precursor cells failed to undergo osteoclastogenesis when treated with IL-1 alone. In contrast, IL-1 dramatically up-regulated osteoclastogenesis by 2.5- to 4-folds in the presence of RANKL and M-CSF. The effect can be significantly blocked by IL-1 receptor antagonist (p < 0.01). Tumor necrosis factor-alpha (TNF-alpha) was undetectable in the culture medium of differentiating osteoclasts induced by IL-1. Adding exogenous TNF-alpha neutralizing antibody had no influence on the IL-1-induced effect as well. These results show that in the absence of stromal cells, IL-1 exacerbates osteoclastogenesis by cooperating with RANKL and M-CSF, while TNF-alpha is not involved in this IL-1-stimulated osteoclast differentiation pathway.

Abstract

This study tests the hypothesis that transcription factor activation by exposure of macrophages to titanium particles can be modulated by the addition of the antiinflammatory cytokine, interleukin 10 (IL-10). The experiments were carried out with primary human monocyte/macrophages that were treated in the presence or absence of IL-10 with and without exposure to titanium particles. The time course for experiments varied from 1 h-5 h for analysis of nuclear protein and up to 48 h for analysis of cytokine release. Transcription factor translocation to the nucleus was analyzed using electrophoretic gel shift assays and cytokine release was quantified by enzyme-linked immunosorbent assay. Addition of titanium particles increased release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta). In addition, titantium particle induced translocation of the transcription factors, NF-kappa B and NF-IL6, in the nucleus within 1 h. Treatment of macrophages with IL-10 prior to exposure to titanium particles decreased translocation of NF-IL6 but did not significantly alter nuclear levels of NF-kappa B. In addition, pretreatment of the cells with IL-10 decreased particle-induced cytokine release. These data show that antiinflammatory cytokines may provide a mechanism by which particle-induced inflammatory response may be modulated in vivo.

Abstract

To test the in vivo effects of interleukin 1 receptor antagonist (IL-1ra) on bone formation and tissue ingrowth using an implantable bone ingrowth chamber that can be infused with test solutions.The bone ingrowth chamber was implanted in the proximal tibia of 10 mature NZW rabbits unilaterally. After an initial osseointegration period, the chambers were emptied of tissue and infused with either 0.05% bovine serum albumin (BSA) in phosphate buffered saline (PBS) or an IL-1ra solution for 4-week periods, which were separated by 4-week periods of no infusion. Tissue samples harvested from each chamber were snap-frozen and examined by histology and immunohistochemistry.The chambers were filled with longitudinally-oriented woven bone in a fibrovascular stroma during periods of infusion of 0.05% BSA in PBS or during periods without infusion. In contrast, infusion of IL-1ra for 4 weeks prevented tissue ingrowth in 4 of 6 chambers, and in 2 chambers exhibiting tissue ingrowth, bone formation was decreased. Bone formation remained at a lower level during the subsequent two 4-week periods without infusion after IL-1ra was discontinued, compared to samples prior to the IL-1ra treatment.The results showed that tissue ingrowth and bone formation were suppressed in an in vivo model by continuous infusion of IL-1ra at an early phase of tissue regeneration and differentiation.

Abstract

Patients undergoing revision total hip arthroplasty frequently require perioperative blood transfusion, increasing the risk for blood-borne disease and anaphylactic and hemolytic reactions. The purpose of this retrospective study was to evaluate the effect of intraoperative blood collection and reinfusion on net blood loss in patients undergoing revision hip arthroplasty.The medical records of 126 patients who had had a revision total hip arthroplasty with intraoperative blood salvage, with use of a collection and reinfusion device, during a twenty-eight-month period were reviewed. For comparison, the medical records of ninety-six patients who had undergone revision hip arthroplasty without intraoperative blood salvage were reviewed. Each of the 222 patients was categorized into a group on the basis of the type of revision.Patients who had a revision of the femoral and acetabular components (Group C) had significantly higher mean intraoperative and total blood loss than did those who had a revision of the femoral component only (Group A [p = 0.009 and p = 0.02, respectively]) or a revision of the acetabular component only (Group B [p = 0.0001 for both]). Total blood loss was not significantly different between Groups A and B. The mean amount of blood reinfused intraoperatively was 356 mL for the patients in Group A, 374 mL for the patients in Group B, and 519 mL for the patients in Group C. Regression analysis showed a significant decrease in net blood loss with intraoperative collection and reinfusion in Groups B (p = 0.002) and C (p = 0.0001) but not in Group A.Intraoperative collection and reinfusion substantially decreased net perioperative blood loss in patients who had a revision of both components (Group C) and in those who had a revision of the acetabular component (Group B). The use of intraoperative blood collection and reinfusion appears to be a valuable method of preserving blood volume in the perioperative period.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medications for relief of pain and inflammation. Recent animal studies using models of fracture healing and bone ingrowth suggest that NSAIDs (both non-selective NSAIDs and selective COX-2 inhibitors) adversely affect these bone-related processes. The dose and time-relationships of these medications and their resulting effects on bone have not yet been fully elucidated. Furthermore, whether COX-2 inhibitors and non-selective NSAIDs lead to clinically relevant adverse effects on bone healing in humans is unknown.

Abstract

Patients requiring bilateral total knee arthroplasties may have both joints replaced simultaneously during one hospitalization (one-stage) or during two separate hospitalizations (two-stage). The goals of the current study were to retrospectively analyze discharge patterns for 91 patients who had one-stage bilateral total knee arthroplasties and 32 patients who had two-stage surgeries, and to quantify their in-hospital costs and their costs if the patients were discharged from the hospital to an inpatient unit. Patients having one-stage and two-stage surgery were similar in age, gender, severity of illness (as measured by the American Society of Anesthesiologists Physical Status score), principal diagnosis, and ethnicity. Using a microcosting approach, the authors found that the average in-hospital costs for one-stage total knee arthroplasty (27,468 US dollars) were significantly lower (by 24%) than for two-stage total knee arthroplasty. However, 38% of patients who had the one-stage bilateral total knee arthroplasties were admitted to an acute rehabilitation unit, which had a mean cost of 6469 US dollars and length of stay of 9 days. In contrast, none of the patients who had the two-stage procedure required acute rehabilitation. Patients who had the two-stage procedure were discharged directly home (or with home health services) 42% of the time, versus 21% for patients who had the one-stage procedure. Patients from both groups were discharged to a skilled nursing facility approximately (1/2) of the time, accruing similar costs. Economic analyses of the one-stage procedure need to consider that these patients will require increased use of acute inpatient rehabilitation after hospital discharge.

Abstract

Nitric oxide (NO) is an effector molecule associated with inflammation, immune function, bone metabolism, and the induction of apoptosis. This study examined the role of NO, peroxynitrite (ONOO(-)), and apoptosis in cases of revision total hip replacements (THRs). We hypothesized that apoptosis and excess production of NO contribute to the inflammatory reaction to orthopedic biomaterial wear debris that is associated with loosening and osteolysis. Periprosthetic membranous specimens were collected from revised cemented acetabular components with simple loosening and ballooning osteolysis. Synovial samples from patients undergoing primary THR were used as controls. The presence of macrophages (CD68(+)) and levels of inducible nitric oxide synthase (INOS), endothelial nitric oxide synthase (EcNOS), ONOO(-) (Nitro, assayed by the amount of nitrated tyrosine residues), and apoptosis (TUNEL staining) were examined using immunohistochemistry. Increased expression for INOS, EcNOS, and ONOO(-) in both the loose/osteolytic and the loose/non-osteolytic groups was observed when compared to the synovium group. There were no significant differences between the loose/osteolytic group and loose/non-osteolytic group for these biologic markers. TUNEL staining showed a significant increase in apoptosis in the loose/osteolytic group compared to the loose/non-osteolytic group and synovial tissues. These findings suggest that NO and NO-derived molecules, such as ONOO(-), may be involved in sustaining the foreign-body reaction to wear debris. NO and ONOO(-) may prove to be useful markers of prosthetic loosening whereas apoptosis may be a marker distinguishing ballooning from simple osteolysis.

Abstract

The value of the Internet to deliver preoperative education would increase if there was variability in questions patients want answered. This study's goal was to have patients consulting an orthopedic surgeon about undergoing either a total hip arthroplasty (THA) or a total knee arthroplasty (TKA) rate the importance of different questions concerning their care.We assembled questions patients might have about joint replacement surgery by analyzing the literature and querying a pilot group of patients and surgeons. Twenty-nine patients considering undergoing THA and 19 patients considering TKR completed a written survey asking them to rate 30 different questions, with a 5 point Likert scale from 1 (least important)--5 (most important).For patients considering THA or TKR, the 4 highest rated questions were: Will the surgery affect my abilities to care for myself?, Am I going to need physical therapy?, How mobile will I be after my surgery?, When will I be able to walk normally again? The mean percentage disagreement was 42% for questions answered by TKR patients and 47% for the THA group. Some patients gave a high rating to questions lowly rated by the rest of the group.Although there was enough agreement to define a core set of questions that should be addressed with most patients considering THA or TKA, some of the remaining questions were also highly important to some patients. The Web may offer a flexible medium for accommodating this large variety of information needs.

Abstract

Osseointegration of porous-coated implants during revision arthroplasty procedures is often impeded due to the presence of residual granuloma, particulate debris, and a sclerotic, dysvascular bone bed. We hypothesized that local infusion of recombinant fibroblast growth factor (FGF-2) would increase bone ingrowth in an in vivo model of tissue differentiation in the rabbit tibia in the presence of phagocytosable polyethylene particles. A drug test chamber (DTC) was implanted in the proximal medial tibial metaphysis of mature rabbits unilaterally. The chamber contained a 1x 1 x 5-mm tunnel for tissue ingrowth, and was connected to an osmotic diffusion pump. FGF-2 was infused at dosages of 0, 0.5, 5, 50, or 500 ng/day for a 3-week period, with subsequent harvesting of the ingrown tissue after each 3-week treatment. The effects of ultrahigh molecular weight polyethylene particles (0.5-microm diameter) on tissue ingrowth were determined by adding particles to the chamber at concentrations of 5.8 x 10(11) (low dose) or 1.7 x 10(12) (high dose) particles/mL, with and without infusion of 50 ng/day of FGF for 3 weeks. The tissue forming in the chamber was harvested after each treatment for histologic processing and morphometric analysis of bone ingrowth. Statistical analysis was performed using parametric tests (ANOVA), nonparametric tests (Kruskal-Wallis test) and post hoc tests. In the absence of particles, infusion of 50 ng FGF-2 per day yielded the greatest amount of bone ingrowth. The high dose of particles suppressed bone ingrowth into the chamber, but the low dose particles did not (p = 0.0002, 95% confidence limits = 9.19-18.80). Infusion of 50 ng FGF-2 per day significantly increased net bone formation in the presence of high-dose UHMWPE particles (p = 0.039, 95% confidence limits = 1.41-6.79). There was a trend for decreased numbers of vitronectin-receptor positive (osteoclast-like) cells with the addition of FGF-2, compared to particles alone (p = 0.08). Local delivery of FGF-2 may prove useful in mitigating the adverse effects of wear debris (e.g., in treating early osteolytic lesions), and facilitating osseointegration of revision total joint replacements in situations where the bone bed is suboptimal and residual particles and granulomatous tissue are present.

Abstract

Infection of a total joint replacement with Mycobacterium tuberculosis is uncommon in North America. This case describes a staphylococcal superinfection that masked an underlying tuberculous infection after total knee replacement and subsequent placement of a cement spacer. The patient had no evidence of M tuberculosis infection elsewhere. The most common explanation for these events is local reactivation of quiescent tuberculosis of the knee joint. The patient was treated successfully with surgical débridement, arthrodesis, and antituberculous medication.

Abstract

Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, particularly cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppression of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proximal tibia of 20 mature New Zealand White rabbits. The DTC provided a continuous 1 x 1 x 5-mm canal for tissue ingrowth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1-100 ng/mL (0.25 microL/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 +/- 0.2 microm diameter, 10(12) particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Osteoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose-response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflammatory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis.

Abstract

The mechanisms underlying the development of osteolysis and aseptic loosening have an impact on the longevity of total hip replacements (THRs). This study examines the specific roles of lymphocytes in the TH1 and TH2 subsets in osteolysis and aseptic loosening of THR. Tissue from periprosthetic regions from patients with loose, cemented acetabular components were used to determine the TH1 and TH2 cytokine profile. Twelve tissue specimens from patients with radiographic signs of osteolysis, and nine tissue specimens from patients with no signs of osteolysis were harvested during revision surgery. Immunohistochemistry using primary antibodies against CD3, interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 was performed on frozen sections to determine the percentage of positive cells for each of the sections. No statistically significant differences in the percentage of positive cells expressing cytokines characteristic of the TH1 pathway (IFN-gamma, IL-2) or TH2 pathway (IL-4, IL-10) were found when comparing osteolytic and non-osteolytic tissues. However, significant numbers of T cells (averaging about 10% of the total cells) and TH1 and TH2 immune cytokines (averaging 3-5% of cells) implicate a possible role for immune processes at the prosthetic interface.

Abstract

To test the effects of intermittent hydrostatic pressure (IHP) on nitric oxide (NO) release induced by shear stress and matrix macromolecule gene expression in human osteoarthritic chondrocytes in vitro.Chondrocytes isolated from cartilage samples from 9 patients with osteoarthritis were cultured and exposed to either shear stress or an NO donor. Nitrite concentration was measured using the Griess reaction. Matrix macromolecule mRNA signal levels were determined using reverse-transcriptase polymerase chain reaction and quantified by imaging analysis software.Exposure to shear stress upregulated NO release in a dose and time-dependent manner. Application of IHP inhibited shear stress induced NO release but did not alter NO release from chondrocytes not exposed to shear stress. Shear stress induced NO or addition of an NO donor (sodium nitroprusside) was associated with decreased mRNA signal levels for the cartilage matrix proteins, aggrecan, and type II collagen. Intermittent hydrostatic pressure blocked the inhibitory effects of sodium nitroprusside but did not alter the inhibitory effects of shear stress on cartilage macromolecule gene expression.Our data show that shear stress and IHP differentially alter chondrocyte metabolism and suggest that a balance of effects between different loading forces preserve cartilage extracellular matrix in vivo.

Abstract

This study addressed the hypothesis that duration and magnitude of applied intermittent hydrostatic pressure (IHP) are critical parameters in regulation of normal human articular chondrocyte aggrecan and type II collagen expression. Articular chondrocytes were isolated from knee cartilage and maintained as primary, high-density monolayer cultures. IHP was applied at magnitudes of 1, 5 and 10 MPa at 1 Hz for durations of either 4 h per day for one day (4 x 1) or 4 h per day for four days (4 x 4). Total cellular RNA was isolated and analyzed for aggrecan and type II collagen mRNA signal levels using specific primers and reverse transcription polymerase chain reaction (RT-PCR) nested with beta-actin primers as internal controls. With a 4x1 loading regimen, aggrecan mRNA signal levels increased 1.3- and 1.5-fold at 5 and 10 MPa, respectively, relative to beta-actin mRNA when compared to unloaded cultures. Changing the duration of loading to a 4x4 regimen increased aggrecan mRNA signal levels by 1.4-, 1.8- and 1.9-fold at loads of 1, 5 and 10 MPa, respectively. In contrast to the effects of IHP on aggrecan, type II collagen mRNA signal levels were only upregulated at loads of 5 and 10 MPa with the 4x4 loading regimen. Analysis of cell-associated protein by western blotting confirmed that IHP increased aggrecan and type II collagen in chondrocyte extracts. These data demonstrate that duration and magnitude of applied IHP differentially alter chondrocyte matrix protein expression. The results show that IHP provides an important stimulus for increasing cartilage matrix anabolism and may contribute to repair and regeneration of damaged or diseased cartilage.

Abstract

Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.

Abstract

Complications in total knee arthroplasty directly related to hardware failure other than polyethylene wear are rare. We report 2 cases of symptomatic screw migration into the joint space from total knee prostheses. In the first case, a screw disengaged from a constrained condylar knee prosthesis. Arthroscopy using standard arthroscopy portals and a small arthrotomy were performed to remove the screw. In the second case, symptomatic screw disengagement and posterior migration from the tibial component of a posterior-stabilized prosthesis occurred. Revision with replacement of the polyethylene insert and locking screw was required.

Abstract

Tissues surrounding failed conventional total hips have been shown to produce inflammatory cytokines that can induce osteoclastic bone resorption. We evaluated the cytokine profiles of tissues from 5 failed metal-on-metal total hip replacements. Serial frozen sections were stained using immunohistochemical and in situ hybridization techniques. Inflammatory and osteoclast-stimulating cytokines were noted in the tissues. As compared to a group of 5 metal-polyethylene hip tissues, we found fewer CD68 positive macrophages, and lower levels of TGF-beta and TNF-alpha, but no differences in CD3 positive lymphocytes, IL-1beta, IL-6 and PDGF-alpha in the metal-on-metal tissues. This may be due, in part to the presence of wear particles from sources other than the bearing surfaces. Thus, cytokines associated with bone resorption and implant loosening may occur in total hips despite the use of alternative bearing materials.

Abstract

This study examined the relationship between acetabular cartilage properties after hemiarthroplasty surgery and surgical variables including femoral head size and position. Nineteen sheep received unilateral hip arthroplasties and were euthanized one year post-operatively to harvest the femora and acetabula. Cartilage histology, biochemistry and material properties were determined from samples located in the superior load-bearing region. Femoral head size mismatch, leg length difference, anterior-posterior and medial lateral offset and anteversion were measured. In the acetabulum. substantial cartilage degradation occurred with widespread librillation and significant changes in the biochemical and material properties compared to the intact contralateral joint. Regression analyses on the surgical variables explained 75-80% of the changes in tissue biochemistry but did not explain the material changes. Head size mismatch and leg length difference were the most significant contributors of the five variables examined and therefore may be critical to successful outcome in hemiarthroplasty.

Abstract

Mechanical loading alters articular cartilage metabolism. However, mechanisms underlying intracellular signaling and communication between cells in response to mechanical stresses remain enigmatic. This study tested the hypothesis that shear stress-induced nitric oxide (NO) production participates in the regulation of matrix protein gene expression. The data presented here demonstrate that exposure of human osteoarthritic chondrocytes to a continuously applied shear stress (1.64 Pa) upregulated NO synthase gene expression and increased NO release by 1.8-, 2.4-, and 3.5-fold at 2, 6, and 24 h, respectively. Exposure of chondrocytes to a short duration of shear stress for 2 h resulted in the release of accumulation of NO in the culture medium. Exposure of chondrocytes to shear stress for 2, 6, and 24 h inhibited type II collagen mRNA signal levels by 27%, 18% and 20% after a constant post-shear incubation period of 24 h. Aggrecan mRNA signal levels were inhibited by 30%, 32% and 41% under identical conditions. Addition of an NO antagonist increased type II collagen mRNA signal levels by an average of 1.8-fold (137% of the un-sheared control) and reestablished the aggrecan mRNA signal levels by an average of 1.4-fold after shear stress (92% of the un-sheared control) (ANOVA p < 0.05). These data support the hypothesis that shear stress-induced NO release may influence the development of degenerative joint diseases by inhibiting matrix macromolecule synthesis.

Abstract

We created three-part unstable intertrochanteric fractures in 6 pairs of aged, osteopenic, human, cadaveric femora. Fractures were reduced and fixed with a Dynamic Hip Screw (DHS) (Synthes, Paoli, PA). Two test groups were evaluated: 1. Fixation with DHS, and 2. Fixation with a DHS and calcium phosphate bone cement (Norian SRS (Skeletal Repair System)) augmentation of the fracture line and posteromedial calcar region of the proximal femur. Each femur was loaded to 1,650 N (2.5 body weight) for 10,000 cycles to simulate postoperative load transmission across the fracture construct during normal gait. The load was further increased successively by one body weight for another 10,000 cycles until failure. We evaluated fixation by measuring the amount of sliding of the lag screw of the DHS (shortening) and stiffness of the overall fracture construct (stability). SRS cement-augmented specimens had less shortening (1 mm versus 17 mm) and twice the initial construct stiffness compared to control specimens.

Abstract

Managing severe structural femoral metaphyseal bone loss in revision total knee arthroplasty is a challenging problem facing the revision knee surgeon. This study assesses the use of large (30 mm) metal distal femoral augments to compensate for severe bone deficiencies. Hospital for Special Surgery scores, Knee Society scores, and range of motion improved after implantation of femoral components with 30-mm distal femoral augments. There was no radiographic evidence of loosening, and no implants had been revised at mean 37-month follow-up. This appears to be an acceptable technique based on the intermediate-term results.

Abstract

Harris-Galante modular acetabular components (Zimmer, Warsaw, IN) have been used widely for primary and revision total hip arthroplasties. The survivorship of this implant has been well documented in the literature. Failure of the liner locking mechanism and subsequent dissociation of the polyethylene liner from the metal-backed shell is a potential cause of failure, however. We report 7 cases of liner dissociation and propose the mode of failure. The result in all cases was a well-fixed metal acetabular shell with a failed locking mechanism, which usually is managed by revision of the entire component. This procedure may be accompanied by the potential loss of acetabular bone stock, which should be replenished.

Abstract

Perioperative knee mechanics currently are evaluated Perioperative knee mechanics currently are evaluated by measuring range of motion. This is an incomplete measurement, however, because the torque applied to achieve the motion is not measured. We hypothesized that a custom goniometer and force transducer could measure the torque required to passively flex a knee through its full range of motion. This measurement was done in the operating room immediately before and after surgery in 20 knees having total knee arthroplasty and 9 having surgery on another limb. Surgery changed the mechanics of 8 knees, whereas unoperated knees remained unchanged. This measurement technique is safe, easy, and repeatable. It improves on the current standard of perioperative knee measurement and can be applied to investigate the effects of surgery and rehabilitation on ultimate knee motion.

Abstract

C-C chemokines are soluble mediators that occur in a periprosthetic granuloma and influence recruitment, localization and activation of inflammatory cells. This study tested effects of titanium and polymethylmethacrylate (PMMA) particles on expression of selected C-C chemokines in cultured human fibroblasts. The C-C chemokines analyzed included monocyte chemoattractant protein-1. 2 (MCP-1. 2), monocyte inflammatory protein-1 alpha (MIP-1 alpha), and regulated on activation, normal T-cell expressed and secreted protein (RANTES). Interleukin-1 beta (IL-1 beta) served as a known stimulator of chemokine release while interleukin-6 (IL-6) expression served as a marker for fibroblast activation. Protein and mRNA signal levels were determined by ELISA and RT-PCR, respectively. The results demonstrated that exposure of fibroblasts to titanium and PMMA particles resulted in increased release of MCP-1 in a dose- and time-dependent manner. After 24 h, titanium particles maximally upregulated MCP-1 release 7-fold while PMMA particles increased MCP-1 levels 2-fold, when compared to unchallenged fibroblasts. MCP-2, MIP-1 alpha and RANTES levels remained unchanged following exposure of fibroblasts to titanium or PMMA particles at any concentration or time point tested. However, IL-1 beta stimulated release of MCP-1, MCP-2, and RANTES, but not MIP-1 alpha from the fibroblasts. IL-1 beta, not particles, exhibited the most prominent effect on MCP-1 mRNA levels. Increased release of MCP-1 from fibroblasts exposed to titanium and PMMA particles coincided with increased release of IL-6. This study suggests that release of chemoattractant factors from fibroblasts localized in periprosthetic membranes enhances the chronic inflammatory process leading to bone resorption and implant loosening.

Abstract

Periprosthetic membranes commonly observed at sites of total joint implant loosening exhibit abundant macrophages and particulate debris. Macrophages phagocytose orthopedic debris and release the pro-inflammatory mediators interleukin-1, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2. Populations of activated lymphocytes are often seen in periprosthetic membranes. These lymphocytes may modulate the monocyte/macrophage response to particulate debris and influence aseptic loosening. In addition, other immunologic agents, such as interleukin-10, are present in tissues harvested from the bone-implant interface of failed total joint arthroplasties. The present study examined the effects of interleukin-10 on polymethylmethacrylate (PMMA) particle challenged human monocyte/macrophages in vitro. Human monocyte/macrophages isolated from buffy coats of five healthy individuals were exposed to 1-10 microm PMMA particles. Interleukin-10 was added to the monocyte/macrophages with and without the addition of PMMA particles. Interleukin-10-induced alterations in monocyte/macrophage metabolism were determined measuring interleukin-6 and tumor necrosis factor-alpha release by the cells following exposure to PMMA particles. Exposure of the monocyte/macrophages to PMMA particles resulted in a dose-dependent release of interleukin-6 and tumor necrosis factor-alpha at 48 h. Interleukin-10 reduced the levels of interleukin-6 and tumor necrosis factor-alpha release by macrophages in response to PMMA particles in a dose-dependent manner. At 48 h, particle-induced interleukin-6 release was inhibited by 60 and 90% with 1.0 and 10.0 ng/ml treatments of interleukin-10, respectively. At 48 h, particle-induced tumor necrosis factor-alpha release was inhibited by 58 and 88% with 1.0 and 10.0 ng/ml treatments of interleukin-10, respectively. Interleukin-10 challenge alone did not significantly alter basal interleukin-6 or tumor necrosis factor-alpha release relative to control cultures. The data presented in this study demonstrate that the anti-inflammatory cytokine, interleukin-10, inhibits monocyte/macrophage release of the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in response to PMMA particle challenge in vitro.

Abstract

Previous studies have attempted to determine whether aseptic loosening and osteolysis are caused by a T cell-mediated type IV hypersensitivity reaction or a nonspecific foreign body reaction involving phagocytic macrophages. The purpose of this study was to examine the role of the B7-CD28 costimulatory pathway (which is indicative of an activated immune response) in loosening and osteolysis of total joint replacements (TJRs). We harvested periprosthetic tissues from 24 loose, cemented, all polyethylene, acetabular components in patients undergoing revision total hip replacement surgery for aseptic loosening. Prostheses were classified radiographically as to whether ballooning, scalloping osteolysis was present or not. Monoclonal antibodies were used to identify macrophages, antigen presenting cells (APCs) expressing B7-1 or B7-2, total T lymphocytes, and T cells expressing CD28 or CTLA-4. The large numbers of positive cells, including macrophages, T cells, and APCs in both groups are substantially higher than previously reported. Macrophages constituted the predominant cell type, the majority of which were APCs. B7-1 was expressed by 18.3% of all cells, and B7-2 was expressed by 61.0% of cells. Despite the fact that there were no statistically significant differences in expression of proteins in the B7-CD28 pathway between the osteolytic and nonosteolytic groups, the magnitude of positive staining suggests that the process of aseptic loosening (not osteolysis) may involve proteins of the B7-CD28 pathway, particularly B7-2. One possible antigenic stimulus is protein-coated particulate wear debris from prosthetic materials.

Abstract

In a prospective consecutive series, 53 revision hip arthroplasties were performed in 51 patients. Pre- and postoperative Duplex ultrasonography examinations were reviewed by an independent, experienced radiologist. Three of 51 patients (53 procedures) had evidence of chronic deep venous thrombosis (DVT) or other venous abnormality preoperatively, yielding an incidence of 5.6%. One (1.9%) patient developed an acute DVT postoperatively despite pharmacological and mechanical preventative measures. These results indicate the use of preoperative ultrasonography as a screening tool prior to revision hip arthroplasty is not warranted based on the low incidence of acute or chronic DVT detected preoperatively. Long-term anticoagulation, when necessary, can be based on the findings of a postoperative scan.

Abstract

This study evaluated the effects of osteogenic protein 1/collagen composite (OP-1/col) mixed with impacted allograft around hydroxyapatite (HA)-coated titanium alloy implants in a canine model. The aim of the study was to test different doses of OP-1 growth factor in a collagen composite for stimulatory effect on allograft incorporation around an implant. Unloaded implants were inserted in each proximal humerus of 16 skeletally mature dogs. The cylindrical implants (4 x 9 mm) coated with HA were initially surrounded by a 3-mm gap into which allograft mixed with OP-1/col was impacted. Two different doses of OP-1 were investigated. In eight animals 325 mg OP-1 protein and 130 mg bovine collagen type I as carrier were mixed with the allograft chips. This composite is identical to the clinically used OP-1 device called Novus. In another eight animals a lower dose of 65 mg OP-1 protein and 130 mg bovine collagen type I was used. Control implants placed in the contralateral humerus were surrounded by allograft mixed with collagen carrier only. The dogs were euthanized at 6 weeks. Implant fixation was determined by push-out testing. Bone ingrowth and bone formation were evaluated by quantitative histomorphometry on serial sections of the bone-implant interface. Impacted allograft together with low-dose OP-1 enhanced bone volume in a zone adjacent to HA-coated titanium alloy implants. The high dose had no effect on bone formation. Mechanical fixation, bone ingrowth, and bone volume in the gap near the original trabecular bone were unaffected by both low and high OP-1/col composite. In this model and observation period, the low dose of OP-1/col composite mixed with impacted allograft has a moderate effect on bone healing around HA-coated implants and no effect on implant fixation.

Abstract

This study examines whether certain psychiatric disorders are associated more closely with adverse life events than other disorders are, and whether some adverse life events are associated with a specific group of disorders (e.g., depressive disorders), but not with other disorders (e.g., anxiety disorders). A probability sample of youth aged 9-17 at 4 sites is used (N = 1,285). Univariate and multivariate logistic regressions identify specific relationships between 25 adverse life events and 9 common child and adolescent psychiatric disorders, measured by the Diagnostic Interview Schedule for Children. Conduct Disorder, Oppositional Defiant Disorder, Major Depressive Disorder, and Dysthymia are significantly associated with many of the adverse life events examined, whereas Attention Deficit/Hyperactivity Disorder, Agoraphobia, and Social Phobia are related to very few. This study suggests that certain psychiatric disorders may be more closely associated with adverse life events than other psychiatric disorders are, and that some adverse life events seem to be related to specific types of disorders.

Abstract

Periprosthetic tissues observed at sites of loose total joint implants exhibit abundant macrophages, lymphocytes, fibroblasts and particulate debris. Macrophages phagocytose orthopaedic debris and release proinflammatory cytokines, chemokines, matrix metalloproteinases and other substances. In addition, other cell types present in tissues harvested from the bone-implant interface are thought to influence periprosthetic bone resorption. The present study examined the effects of polymethylmethacrylate (PMMA), cobalt chrome molybdenum alloy (CoCr), and titanium-alloy particle challenge on macrophages co-cultured with lymphocytes in vitro. Potential synergistic effects of lymphocytes on macrophage activation were determined by measuring interleukin-6 and tumor necrosis factor-alpha release following exposure to orthopaedic biomaterial particles. Exposure of macrophages or macrophages co-cultured with lymphocytes to all three types of particles resulted in increased release of interleukin-6 and tumor necrosis factor-alpha at 48 h, when compared to macrophages or macrophages co-cultured with lymphocytes, respectively, cultured in the absence of particles. Lymphocytes isolated from periprosthetic tissues secreted increased basal levels of cytokines relative to peripheral blood lymphocytes. Higher doses of PMMA and titanium-alloy particles stimulated increased levels of cytokine release in the macrophage and macrophage/lymphocyte groups. In contrast, a higher dose of CoCr particles (0.075% v/v) was not as effective as the 0.015% v/v dose, indicating probable CoCr toxicity. The macrophage/lymphocyte co-culture did not show synergism between the two types of cells with respect to cytokine release. T-cells at the bone-implant interface may alter the biological response to particulate debris.

Abstract

CCR7, along with L-selectin and LFA-1, mediates homing of T cells to secondary lymphoid organs via high endothelial venules (HEV). CCR7 has also been implicated in microenvironmental positioning of lymphocytes within secondary lymphoid organs and in return of lymphocytes and dendritic cells to the lymph after passage through nonlymphoid tissues. We have generated mAbs to human CCR7, whose specificities correlate with functional migration of lymphocyte subsets to known CCR7 ligands. We find that CCR7 is expressed on the vast majority of peripheral blood T cells, including most cells that express adhesion molecules (cutaneous lymphocyte Ag alpha(4)beta(7) integrin) required for homing to nonlymphoid tissues. A subset of CD27(neg) memory CD4 T cells from human peripheral blood is greatly enriched in the CCR7(neg) population, as well as L-selectin(neg) cells, suggesting that these cells are incapable of homing to secondary lymphoid organs. Accordingly, CD27(neg) T cells are rare within tonsil, a representative secondary lymphoid organ. All resting T cells within secondary lymphoid organs express high levels of CCR7, but many activated cells lack CCR7. CCR7 loss in activated CD4 cells accompanies CXC chemokine receptor (CXCR)5 gain, suggesting that the reciprocal expression of these two receptors may contribute to differential positioning of resting vs activated cells within the organ. Lymphocytes isolated from nonlymphoid tissues (such as skin, lung, or intestine) contain many CD27(neg) cells lacking CCR7. The ratio of CD27(neg)/CCR7(neg) cells to CD27(pos)/CCR7(pos) cells varies from tissue to tissue, and may correlate with the number of cells actively engaged in Ag recognition within a given tissue.

Abstract

The local delivery of exogenous growth factors may help achieve a stable, long-lasting prosthetic interface around primary and revision joint replacements. This study examines the effects of local infusion of transforming growth factor beta (TGFbeta) in an in vivo model of tissue differentiation within bone. The Drug Test Chamber was implanted in the proximal medial tibial metaphysis of 8 mature rabbits unilaterally. The chamber contained a 1 x 1 x 5 mm canal for tissue ingrowth. The chamber was connected to an osmotic diffusion pump via polyvinyl tubing. 3.5 microg of recombinant TGFbeta1 was infused for 1 day or 1 week with subsequent harvesting of the ingrown tissue after 3 weeks. Each TGFbeta treatment was followed by two, 3-week infusions of carrier alone and harvesting of the ingrown tissue. TGFbeta for 1 day increased, and TGFbeta for 1 week decreased the percentage of bone in the chamber, compared to the initial control harvest after carrier alone. These changes, however, did not reach statistical significance. The number of vitronectin receptor positive cells in total, adjacent to bone and away from bone was higher after treatment with TGFbeta for 1 day, compared to 1 week. In an "unperturbed" bone ingrowth system (i.e., if bone ingrowth is not initially suppressed by other stimuli), this dose of TGFbeta did not enhance bone ingrowth using the DTC model.

Abstract

Periprosthetic granulomatous membranes consisting of fibroblasts, macrophages, lymphocytes, foreign body giant cells, and abundant particulate debris occur at sites of implant loosening. Previous studies demonstrate that fibroblasts respond to particulate debris through the release of interleukin-6 (IL-6), prostaglandin E(2), and matrix metalloproteinases in vitro. C-C chemokines are observed in granulomatous tissue surrounding loosened prosthetic implants and are released by macrophages and fibroblasts in response to particle challenge in vitro. This study tested the hypothesis that G protein activity is required for fibroblast activation by titanium and polymethylmethacrylate (PMMA) particles, and that inhibition of G protein activity would alter IL-6 and and monocyte chemoattractant protein-1 (MCP-1) release from activated fibroblasts. The specific inhibitor of G protein activity, pertussis toxin, was added to the fibroblasts to examine the effects of G protein activity with respect to the production of IL-6 and MCP-1 by orthopedic biomaterial-challenged fibroblasts in vitro. Interleukin-1beta (IL-1beta), a proven activator of MCP-1 and interleukin-6, was used as a positive control. Exposure of fibroblasts to titanium and polymethylmethacrylate (PMMA) particles resulted in a dose-dependent release of MCP-1 and IL-6. Challenge with PMMA particles at doses of 0.150%, 0.300%, and 0.600% vol/vol increased the release of interleukin-6 by 7-, 19-, and 22-fold, respectively, compared to fibroblasts exposed to serum-free culture medium alone at 24 h. Challenge with PMMA particles at doses of 0.075%, 0.150%, 0.300%, and 0.600% vol/vol increased the release of MCP-1-6 by 2.5-, 3.6-, 4. 3-, and 4.5-fold, respectively, compared to fibroblasts exposed to serum-free culture medium alone. Challenge with titanium particles at concentrations of 0.075%, 0.150%, 0.300%, and 0.600% vol/vol increased the release of interleukin-6 by 2.6-, 6.4-, 9.6-, and 10. 0-fold, respectively, compared to fibroblasts exposed to serum-free culture medium alone at 24 h. Challenge with titanium particles at concentrations of 0.038%, 0.075%, 0.150%, 0.300%, and 0.600% vol/vol increased the release of MCP-1 by 2.9-, 3.1-, 5.8-, 5.4-, and 5. 8-fold, respectively, compared to fibroblasts exposed to serum-free culture medium alone. Pretreatment of fibroblasts with pertussis toxin inhibited the release of interleukin-6 and MCP-1 from PMMA and titanium particle challenged fibroblasts in a dose-dependent manner. PMMA particle induced fibroblast IL-6 release was inhibited by 23.6% and 35.3% with 20- and 200-ng/mL doses of pertussis toxin, respectively. Titanium particle induced fibroblast IL-6 release was inhibited by 48.2% and 56.3% with 20- and 200-ng/mL doses of pertussis toxin, respectively. PMMA particle-induced fibroblast MCP-1 release was inhibited by 36.0%, 50.4%, and 60.1% with 2-, 20- and 200-ng/mL doses of pertussis toxin, respectively. Titanium particle-induced fibroblast MCP-1 release was inhibited by 15.5%, 53.2%, and 64.6% with 2-, 20-, and 200-ng/mL doses of pertussis toxin, respectively. This study suggests that fibroblasts localized in periprosthetic membranes are a source of macrophage chemoattractant factors and proinflammatory mediators that may influence granuloma formation and lead to periprosthetic bone resorption. Furthermore, this study shows that G proteins are involved in particle-induced fibroblast activation, as evidenced by decrease levels of particle induced IL-6 and MCP-1 release following pertussis toxin treatment. (c) 2000 John Wiley & Sons, Inc.

Abstract

The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

Abstract

Orthopaedic wear debris induces release of bone-resorbing factors from macrophages and fibroblasts. However, the extent to which elemental metallic particles induce bone cells to express factors contributing to implant loosening remains unclear. This study showed that exposure of MG-63 osteoblast-like cells to titanium particles at a concentration of 0.30% v/v resulted in a 15-fold increase in IL-6 release into the culture medium after 24 hours, when compared with cells without particles. Northern blots revealed that exposure of MG-63 cells to titanium particles at a concentration of 0.30% v/v for 24 hours increased IL-6 mRNA signal levels by 9.6-fold, when compared with control cultures. Pretreatment of MG-63 cells with cytochalasin B prevented the particle-induced increase of IL-6 expression but did not alter the basal level of IL-6 release from cells cultured in the absence of particles. The protein kinase C inhibitor, H7, and the serine/threonine kinase inhibitor, genistein, abolished the particle-induced increase in IL-6 release at a concentration of 100 microM for each compound. In contrast, an inhibitor of protein kinase A, HA1004, had no effect on the particle-induced increase in IL-6 release. The transcription factors, nuclear factor IL-6 and nuclear factor kappa B, translocated into the nucleus within 1 hour of particle exposure. This study showed that osteoblast-like cells respond to titanium particles through increased expression of the proinflammatory cytokine, IL-6, in a process requiring phagocytosis and intracellular signaling pathways. These results suggest that osteoblasts play a direct role in implant loosening because of localized release of soluble mediators such as interleukin-6.

Use of COX-2 specific inhibitors in operative and nonoperative management of patients with arthritisORTHOPEDICSGoodman, S. B.2000; 23 (7): S765-S768

Abstract

Arthritis is a major burden on society and the individual. Arthritis affects all age groups and races, and is more prevalent in women than men by approximately 1.65:1. Nearly one half of people aged > or = 65 years report the presence of arthritic symptoms; however, by no means is arthritis a disease of only the elderly. The burden of arthritis will continue to increase due to expected future increases in the size and age of the general population. Currently, the total costs of medical care and lost wages due to arthritis are in excess of 64 billion dollars per year in the United States. For the individual, arthritis may cause substantial pain, impair mobility, curtail physical activity, and have a negative impact on mental health. The two most common forms of arthritis, osteoarthritis and rheumatoid arthritis, have major health complications. From the perspective of the orthopedic surgeon, the aim of treatment of arthritic conditions includes early, accurate diagnosis and appropriate treatment to minimize pain and maximize function. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used as part of the medical management of patients with arthritis. These medications are effective in mitigating pain and inflammation associated with arthritis. However, side effects (most notably of the gastrointestinal tract) have limited the more widespread use of NSAIDs. The newer cyclooxygenase-2 (COX-2) inhibitors have proven to be efficacious and have demonstrated fewer gastrointestinal adverse effects. Furthermore, COX-2 inhibitors do not appear to adversely affect platelet function. For these reasons, consideration may be given to using COX-2 perioperatively, however, drug interactions must be closely monitored.

Abstract

This study analysed MIF mRNA and protein expression in human macrophages exposed in vitro to polymethylmethacryate and titanium alloy particles. MIF levels released from macrophages without exposure to particles were in the range of 2-4 ng/ml. Exposure of macrophages to particles as demonstrated increased MIF release at 0. 075%-0.225% v/v particle concentration, which was maximal at 12-24 h. MIF mRNA signal levels in cells with and without particles at a concentration of 0.075% showed no significant differences in a time course experiment. The profile of MIF release in response to increasing particle concentration coincided with increased release of lactate dehydrogenase. The viability of the cells was unchanged by the addition of particles as determined by 3H-thymidine uptake. These data suggest that MIF expression may represent an independent macrophage response to locally high particle concentrations.

Efficacy of postoperative blood salvage following total hip arthroplasty in patients with and without deposited autologous units.journal of bone and joint surgery. American volumeGrosvenor, D., GOYAL, V., Goodman, S.2000; 82-A (7): 951-954

Abstract

Patients undergoing total hip replacement routinely receive perioperative blood transfusions, increasing their risk of blood-borne disease, isoimmunization, anaphylactic reaction, and hemolytic reaction. The purpose of this retrospective, case-control study was to evaluate the effect of postoperative blood salvage on the need for allogeneic transfusion following total hip replacement.We reviewed the medical records of ninety consecutive patients who, during a twelve-month period, had undergone unilateral, elective total hip replacement that included use of a postoperative blood salvage device. For comparison, we reviewed the medical records of ninety consecutive patients who had undergone total hip replacement without postoperative blood salvage. Overall, 156 patients had complete medical records and were included in the study.Eight (10 percent) of the patients who had been treated with a drain and seventeen (23 percent) of the patients who had been treated without a drain received allogeneic transfusions. Of the nineteen patients who had not deposited autologous blood, all six without postoperative blood salvage required allogeneic transfusion. With control for other variables in the model, regression analysis showed a significantly increased risk of allogeneic transfusion among patients who had undergone total hip replacement without postoperative blood salvage (p = 0.0028) and without having predonated autologous units (p = 0.0001).Despite a limited sample size, the study results showed that postoperative blood salvage significantly reduced the risk of allogeneic transfusion among patients managed with total hip replacement, whether or not they had deposited autologous blood (p < 0.0001). With control for donated units, age, gender, preoperative hematocrit, intraoperative blood loss, and cementless technique, patients who were treated without postoperative blood salvage were approximately ten times more likely to require allogeneic transfusion than were patients who had a drain.

Abstract

Debonding of the cement-implant interface has been hypothesized to be the leading initial indicator of failed total hip prostheses. Many attempts have been made to increase the bond strength of this interface by precoating the implant, increasing the implant's surface roughness, and creating macro-grooves or channels on the implant. However, each of these approaches introduces new complications. This study introduces a unique silane coupling agent used to chemically bond the bone cement to the implant. Cylindrical cobalt-chrome samples were treated with the silane coupling agent, bonded to polymethylmethacrylate, and pushed out to failure. The mean shear strengths were compared to the failure strengths of untreated samples. Half of the specimens were tested immediately following cement curing, and the other half were tested after immersion in saline solution for 60 days. The mean shear strength of the silane-coated samples ranged from 18.2 to 24.1 MPa, and the mean shear strength of the uncoated samples ranged from 7.6 to 15.0 MPa. The increase in strength following silane coating noted in this study may increase the longevity of the implant by decreasing debonding at the interface and, therefore, subsequent failure due to loosening.

Abstract

In a prospective, consecutive series, 41 total hip arthroplasties were performed in 27 small-proportioned patients with small femoral dimensions. The 17 female and 10 male patients averaged 23.6 years (range, 14-47 years), and the mean height and weight were 157 cm (range, 132-183 cm) and 53.5 kg (range, 36-84 kg). The most common preoperative diagnosis was juvenile rheumatoid arthritis in 18 patients (28 hips). Most patients were severely disabled in their daily activity, and 68% of the patients were classified as Charnley functional class C. The femoral implants consisted primarily of the proximally porous-coated miniature Anatomic Medullary Locking femoral component (AML/CDH, Depuy, Warsaw, IN) in 33 hips in 22 patients (average stem diameter, 9.5 mm; range, 8-12.0 mm). A porous ingrowth acetabular cup fixed with screws was used in all procedures. At an average follow-up of 51 months, Harris Hip Scores improved significantly from 34 points (range, 0-65 points) preoperatively to 85 points (range, 33-100 points) after arthroplasty. There were no intraoperative complications. There was 1 revision because of femoral implant loosening. Three cementless femoral components showed evidence of nonprogressive subsidence. One patient had significant bilateral acetabular component polyethylene wear and underwent revision. All other femoral and acetabular components were radiographically stable. The relief of pain and improvement of function were dramatic. The miniature AML/CDH femoral component, combined with an uncemented acetabular cup, provides a promising, off-the-shelf alternative in small-proportioned patients.

Abstract

The differentiation and maturation of macrophages and osteoclasts at the prosthetic interface in cases of implant loosening are poorly understood. Using histochemical and immunohistochemical staining methods, we compare macrophage differentiation in tissues from revised hip replacements in patients with specific clinical-radiological appearances. Periprosthetic tissues were harvested from 12 cemented acetabular and 12 cemented femoral components in 24 patients undergoing revision hip replacement. The prostheses were all radiographically and clinically loose. Six acetabular and six femoral components demonstrated radiographic ballooning osteolysis. Serial 6 microm frozen sections of the periprosthetic tissues were processed with hematoxylin and eosin for general tissue morphology, and analyzed for the presence of tartrate resistant acid phosphatase (TRAP, an osteoclast marker). Immunoperoxidase staining using monoclonal antibodies to CD68 (macrophages and osteoclasts) and CD51 (the alpha chain of the vitronectin receptor, an osteoclast marker) was also performed. Approximately 8-30% of the total cells in the tissues were positive for TRAP and the vitronectin receptor, and comprised a subset of the CD68 positive macrophages and macrophage polykaryons. However, there were no statistically significant differences between specific groups (femoral vs. acetabular, osteolysis vs. no osteolysis) for the numbers or percentages of macrophages or osteoclast-like cells. Once prosthetic loosening has occurred, few differences in the macrophage-osteoclast profile of tissues from different periprosthetic locations, with and without osteolysis, are noted. This suggests a final common biologic pathway for periprosthetic bone resorption, once implant loosening has transpired.

Abstract

We implanted bone harvest chambers (BHCs) bilaterally in ten mature male New Zealand white rabbits. Polyethylene particles (0.3+/-0.1 microm in diameter, 6.4 x 10(12) particles/ml) were implanted for two, four or six weeks bilaterally in the BHCs, with subsequent removal of the ingrown tissue after each treatment. In addition to the particles, one side also received 1.5 microg of recombinant transforming growth factor beta1 (TGFbeta1). At two weeks, the bone area as a percentage of total area was less in chambers containing TGFbeta compared with those with particles alone (7.8+/-1.3% v 16.9+/-2.7% respectively; 95% confidence interval (CI) for difference -14.0 to -4.30; p = 0.002). At four weeks, the percentage area of bone was greater in chambers containing TGFbeta compared with those with particles alone (31.2+/-3.4% v 22.5+/-2.0% respectively; 95% CI for difference 1.0 to 16.4; p = 0.03). There were no statistical differences at six weeks, despite a higher mean value with TGFbeta treatment (38.2+/-3.9% v 28.8 +/-3.5%; 95% CI for difference -4.6 to 23.3; p = 0.16). The number of vitronectin-receptor-positive cells (osteoclast-like cells) was greater in the treatment group with TGFbeta compared with that with particles alone; most of these positive cells were located in the interstitium, rather than adjacent to bone. TGFbeta1 is a pleotropic growth factor which can modulate cellular events in the musculoskeletal system in a time- and concentration-dependent manner. Our data suggest that there is an early window at between two and six weeks, in which TGFbeta may favourably affect bone ingrowth in the BHC model. Exogenous growth factors such as TGFbeta may be a useful adjunct in obtaining osseointegration and bone ingrowth, especially in revisions when there is compromised bone stock and residual particulate debris.

Abstract

Periprosthetic membranes commonly observed at sites of total joint implant loosening exhibit abundant macrophages and particulate debris. Macrophages phagocytose orthopedic debris and release the pro-inflammatory mediators interleukin-1, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2. In addition, other immunologic agents, such as interferon-gamma, are present in tissues harvested from the bone-implant interface of failed orthopedic implants. The present study examined the effects of interferon-gamma on polymethylmethacrylate (PMMA) particle-challenged monocyte/macrophages in vitro. The effects of interferon-gamma were determined by measuring interleukin-6 and tumor necrosis factor-alpha release by primary human monocyte/macrophages following exposure to PMMA particles. Exposure of the monocyte/macrophages to PMMA particles resulted in a dose-dependent release of interleukin-6 and tumor necrosis factor-alpha at 48 h. The interleukin-6 release in response to PMMA particle challenge was stimulated by 76% and 127% in the presence of 1.0 and 10.0 ng/mL of interferon-gamma, respectively. Interferon-gamma challenge alone did not alter interleukin-6 release relative to controls. In contrast to interleukin-6, interferon-gamma challenge stimulated tumor necrosis factor-alpha release in a dose-dependent manner. In the presence of particles, addition of 1.0 and 10.0 ng/mL of interferon-gamma resulted in 17% and 171% increases in the levels of tumor necrosis factor-alpha release, respectively, relative to cultures challenged solely with particles. Blocking antibody to IFN-gamma inhibited the effect of IFN-gamma on particle-induced interleukin-6 and tumor necrosis factor-alpha release. The data presented in this study demonstrate that the immunologic modulator interferon-gamma exacerbates monocyte/macrophage release of the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in response to PMMA particle challenge in vitro.

Abstract

This study reports on the effects of phagocytosable particles on proinflammatory mediator release in an animal model. Bone harvest chambers (BHCs) were implanted bilaterally into mature rabbits; phagocytosable ultrahigh molecular weight polyethylene (UHMWPE) and polystyrene (PS) particles, and the carrier sodium hyaluronate (HE) were tested for their ability to stimulate proinflammatory mediator release. Tissues were harvested after 3, 4, or 6 weeks. Retrieved tissues were placed into culture medium. The release of the proinflammatory mediators interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha) into the culture medium was assessed using bioassays. DNA content and dry weights were also measured. The maximal biological response to the PE particles with respect to TNF-alpha and IL-1beta was observed at three weeks with 11- and fivefold stimulations over controls, respectively. The maximal response to PE particles with respect to IL-6 was observed at 4 weeks with a twofold stimulation over controls. Similar patterns were seen with PS particles; however, PE particles stimulated higher cytokine release. PE particles stimulated the expression of IL-1beta, IL-6, and TNF-alpha in the BHC model. Cell culture and human retrieval studies also implicate these proinflammatory mediators in loosening and osteolysis of total joint replacements. Thus, the BHC is a useful in vivo model to document the effects of particles on the evolution of biological responses to particulate debris.

Abstract

Cytokines that regulate monocyte migration were found in membrane tissue surrounding loosened prosthetic implants. Monocyte migration inhibition factor (MIF) is able to inhibit macrophage migration. Monocyte chemoattractant protein (MCP) and macrophage inflammatory protein (MIP) are potent macrophage chemoattractants. These cytokines may be expressed as part of the foreign body response to prosthetic particulate debris. Chemotaxis analysis and macrophage activation experiments were performed to determine the effects of MIF, MCP-1, and MIP-1alpha on macrophage migration and activation in vitro. We demonstrated that MIF had its maximal migration inhibitory effect for unchallenged and particle challenged macrophages at 1 ng/mL. MCP-1 and MIP-1alpha stimulated macrophage chemotaxis maximally at 1 to 10 ng/mL. Dose-response studies with MIF, MCP-1, and MIP-1alpha demonstrated that these cytokines did not modulate activation of unchallenged or particle challenged macrophages as evaluated by IL-6 and TNF-alpha release. However, these cytokines do not appear to affect macrophage release of proinflammatory mediators in vitro.

Abstract

Loosening of the implant after total joint arthroplasty remains a serious problem. The activation of macrophages by wear debris from implants, mediated by the release of cytokines that elicit bone resorption, may lead to loosening. The purpose of the present study was to elucidate the mechanisms of macrophage activation by titanium particles from the components of implants and to identify the signaling pathways involved in particle-mediated release of cytokines.Macrophages were isolated from mononuclear leukocytes obtained from healthy human donors and were exposed to titanium-alloy particles that had been obtained from periprosthetic membranes collected at revision total joint arthroplasties and then enzymatically prepared. The experimental protocols included examination of the effects of the inhibition of phagocytosis and the binding of antibodies to macrophage complement receptors on particle-induced macrophage activation. The release of the proinflammatory cytokines TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) was used to assess macrophage activation. The signaling pathways involved in the induction of cytokine release were analyzed by identification of phosphorylated proteins with use of the Western blot technique and by translocation of the transcription factors nuclear factor-kappa B (NF-kappaB) and nuclear factor-interleukin-6 (NF-IL-6) into the nuclear protein fraction with use of electrophoretic mobility shift assays. The role of serine/threonine and tyrosine kinase pathways in the activation of nuclear factors and the release of cytokines was examined with use of selective pharmacological agents.Exposure of macrophages to titanium-alloy particles in vitro for forty-eight hours resulted in a fortyfold increase in the release of TNF-alpha and a sevenfold increase in the release of IL-6 (p<0.01). Phagocytosis of particles occurred in approximately 73 percent of the macrophages within one hour of exposure. Pretreatment of the macrophages with cytochalasin B reduced phagocytosis by 95 percent but did not reduce the release of TNF-alpha or IL-6. Thus, phagocytosis of particles was not necessary for induction of the release of TNF-alpha or IL-6 in the cultured macrophages. Ligation of the macrophage CD11b/CD18 receptors by integrin-specific antibodies also increased the release of TNF-alpha and IL-6. Antibodies to CD11b/ CD18 receptors (macrophage Mac-1 receptors) reduced phagocytosis of particles by 50 percent (p<0.05). (The CD11b/CD18 macrophage receptor is the macrophage receptor for the complement component CR3bi. The CD11b/CD18 macrophage receptor can also bind to ICAM-1 and ICAM-2. CD is the abbreviation for cluster of differentiation, and ICAM is the abbreviation for intercellular adhesion molecule.) Inhibition of phagocytosis was not accompanied by a decrease in the release of TNF-alpha and IL-6. Blocking RNA synthesis with actinomycin D or preventing protein synthesis with cycloheximide abolished or decreased particle-induced release of TNF-alpha and IL-6 from the macrophages. Macrophage release of TNF-alpha and IL-6 in response to particles coincided with increased tyrosine phosphorylation and mitogen-activated protein kinase activation. Inhibition of tyrosine and serine/threonine kinase activity decreased the particle-induced release of cytokines. Exposure of macrophages to either titanium-alloy particles or to antibodies to the receptor proteins CD11b and CD18 for thirty minutes activated the transcription factors NF-kappaB and NF-IL-6. Inhibition of particle phagocytosis did not block activation of the transcription factors. However, inhibition of tyrosine and serine/threonine kinase activity decreased the activation of NF-kappaB and NF-IL-6.These data suggest that particle induced macrophage release of TNF-alpha and IL-6 does not require phagocytosis but is dependent on tyrosine and serine/threonine kinase activity culminating in activation of

Abstract

Particulate wear debris is associated with periprosthetic inflammation and loosening in total joint arthroplasty. We tested the effects of titanium alloy (Ti-alloy) and PMMA particles on monocyte/macrophage expression of the C-C chemokines, monocyte chemoattractant protein-1 (MCP-1), monocyte inflammatory protein-1 alpha (MIP-1alpha), and regulated upon activation normal T expressed and secreted protein (RANTES). Periprosthetic granulomatous tissue was analysed for expression of macrophage chemokines by immunohistochemistry. Chemokine expression in human monocytes/macrophages exposed to Ti-alloy and PMMA particles in vitro was determined by RT-PCR, ELISA and monocyte migration. We observed MCP-1 and MIP-1alpha expression in all tissue samples from failed arthroplasties. Ti-alloy and PMMA particles increased expression of MCP-1 and MIP-1alpha in macrophages in vitro in a dose- and time-dependent manner whereas RANTES was not detected. mRNA signal levels for MCP-1 and MIP-1alpha were also observed in cells after exposure to particles. Monocyte migration was stimulated by culture medium collected from macrophages exposed to Ti-alloy and PMMA particles. Antibodies to MCP-1 and MIP-1alpha inhibited chemotactic activity of the culture medium samples. Release of C-C chemokines by macrophages in response to wear particles may contribute to chronic inflammation at the bone-implant interface in total joint arthroplasty.

Abstract

Total hip replacement is a successful, time-proven surgical procedure for reconstruction of the arthritic hip joint. The state of the bone-implant interface is crucial to the long-term integration and durability of hip replacements whether cemented or cementless. This review summarizes current clinical implant retrieval and animal research in hip-joint reconstruction. Future research must attempt to extend the longevity of hip replacements to avoid complex revision surgery.

Abstract

The interactions between the different cell types in periprosthetic tissue are still unclear. We used a non-contact coculture model to investigate the effects of polymethylmethacrylate (PMMA) particles and human macrophage-derived soluble mediators on fibroblast activation. Macrophages were either exposed or not exposed to phagocytosable PMMA particles, but fibroblasts were not. Increasing numbers of macrophages were tested in cocultures in which the fibroblast cell number was held constant and cultures of macrophages alone were used for comparison of cytokine release. We used the release of interleukin-1 beta (IL-1beta), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), lysosomal enzyme and metalloproteinase activity to assess the cultivation of macrophages and fibroblasts. In cocultures, IL-6 release was increased 100-fold for both unchallenged and particle-challenged cultures when compared with macrophage cultures alone. Furthermore, particle-challenged cocultures had threefold higher IL-6 levels than unchallenged cocultures. Release of TNF-alpha was similar in cocultures and in macrophage cultures. IL-1beta release in cocultures was independent of the macrophage-fibroblast ratio. Lysosomal enzyme activity and metalloproteinase activity were increased in cocultures. Our data show that macrophages and fibroblasts in coculture significantly increase the release of IL-6 and to a less degree other inflammatory mediators; particle exposure accentuates this effect. This suggests that macrophage accumulation in fibrous tissue may lead to elevated IL-6 levels that are much higher than those caused by particle activation of macrophages alone. This macrophage-fibroblast interaction represents a novel concept for the initiation and maintenance of the inflammatory process in periprosthetic membranes.

Abstract

Postoperative knee flexion in patients undergoing Insall-Burstein-II total knee arthroplasty at 2 years was evaluated regarding two basic questions: what groups of patients gain or lose the most flexion and what groups of patients have the best or worst postoperative flexion. Thirteen preoperative variables (maximum flexion, flexion arc, tibiofemoral angle, quadriceps strength, extensor lag, Knee Society score, Knee Society patient assessment, gender, age, height, weight, diagnosis, and surgeon) and four postoperative variable (leg length change, tibiofemoral angle, distance from patella to the joint line, and the tibial prosthesis anteroposterior translation on a lateral radiograph) were used in an attempt to explain postoperative flexion. The analysis was performed on 164 consecutive Insall-Burstein-II total knees in which the data were gathered prospectively on a time oriented medical record database. A regression tree analysis was used to identify several groups of patients, characterized by preoperative factor values, who had markedly above average performance on postoperative flexion. The preoperative factors identified include preoperative flexion, flexion arc, tibiofemoral angle, extensor lag, diagnosis, and age. The only postoperative variable of significance was tibiofemoral angle. Among the potential determinants of postoperative flexion that failed to appear predictive were the Knee Society scores and surgeon. Preoperative flexion is known to be a critical determinant of postoperative flexion in total knee replacement. However, in the current study, preoperative flexion accounted for only half of the difference between the best (122 degrees) and the worst (88 degrees) group, as determined with regression tree analysis.

Abstract

We exposed human macrophages isolated from the peripheral blood of healthy donors to metal and bone-cement particles from 0.2 to 10 microm in size. Zymography showed that macrophages exposed to titanium alloy and polymethylmethacrylate (PMMA) particles released a 92- and 72-kDa gelatinase in a dose- and time-dependent manner. Western immunoblotting confirmed that the 92- and 72-kDa gelatinolytic activities corresponded to matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9, MMP-2), respectively. Western immunoblotting also indicated that titanium alloy and PMMA particles increased the release of MMP-1. Northern blotting showed elevated mRNA signal levels for MMP-1, MMP-2, and MMP-9 after exposure to both types of particle. Collagenolytic activity also increased in the macrophage culture medium in response to both types of particle. Our findings support the hypothesis that macrophages release MMPs in proportion to the amount of particulate debris within periprosthetic tissues.

Abstract

The biologic effects of wear debris are an important factor limiting the longevity of total joint replacements. In vivo, in vitro, and tissue retrieval studies have underlined a central role for the macrophage in the etiology of loosening and periprosthetic osteolysis. Wear particles from the materials used for total joint replacement activate macrophages to secrete proinflammatory factors. Complex interactions between macrophages and other cells stimulate bone resorption and suppress bone formation at the prosthetic interface. To improve the long term outcome of joint replacements, future research must find innovative approaches to minimize the production and biologic effects of wear debris.

Abstract

Clinical studies suggest a role for polyethylene (PE) wear debris in the pathogenesis of osteolysis and loosening of total joint replacements. In this study, submicron particles of ultrahigh molecular weight PE (UHMWPE) were placed around pressfit tibial hemiarthroplasties in rabbits to determine the biological reaction. After 6 months the periprosthetic tissue was harvested and characterized biochemically by measuring the extracellular matrix macromolecules, collagen, and glycosaminoglycan (GAG) and quantifying the expression of inflammatory/osteolytic mediators [prostaglandin E2 (PGE2), hexosaminidase, transforming growth factor beta (TGF beta), and interleukins-6 and -1 (IL-6, IL-1)]. Particle exposure resulted in a decrease in levels of total extracellular matrix molecules including a 53% decrease in total GAG (p < 0.05) and a 74% decrease in total collagen (p < 0.005). Collagen content remained significantly decreased when normalized for cellularity (DNA content). Total TGF beta release exhibited a downward trend (p = 0.06) in the particle exposed group. Hexosaminidase and PGE2 levels did not show a difference between groups; however, when normalized for cellularity, PGE2 values exhibited an upward trend in the particle exposed group (p = 0.1). IL-6 was undetected by bioassay and ELISA. Previous studies emphasized that PE debris enhances the degradation of bone. The data from this in vivo model suggest that submicron UHMWPE particles may also act to inhibit biosynthetic pathways of bone and mesenchymal tissue. Decreased levels of collagen, GAG, and TGF beta expression may indicate suppression of bone formation, possibly through a downregulation of osteoblast activity.

Abstract

Nitric oxide (NO) is a ubiquitous molecule that has been associated with inflammation, arthritis, autoimmune disease, bone resorption, and other biological processes. Elucidating the role of NO at the bone-implant interface may further our understanding of the biological processes of osseointegration, loosening, and osteolysis. This study demonstrates the use of a molecular biological technique to investigate the possible role of NO in prosthetic loosening and periprosthetic bone resorption following total hip arthroplasty. Periprosthetic tissue from 12 patients undergoing revision hip arthroplasty was harvested and total ribonucleic acid (RNA) was extracted. In six of the 12 patients, multiple samples from different anatomic locations along the same interface were studied. To estimate the amount of NO present in the tissues in vivo, the level of inducible NO synthase (iNOS) messenger RNA (mRNA) was determined using a ribonuclease (RNase) protection assay. Inducible NOS mRNA was detected in every tissue sample: there was no correlation between iNOS mRNA levels and clinical loosening or osteolysis. Analysis of multiple tissue samples from the same prosthetic component revealed that the levels of iNOS mRNA vary greatly, confirming the heterogeneous nature of the interface.

Abstract

The condylar constrained total knee arthroplasty was performed on 29 patients undergoing 33 procedures and were reviewed clinically and radiographically at an average follow-up of 5 years (range, 2-10 years). There were 21 women and 8 men. The average age at the time of surgery was 70 years (range, 32-84). Of the 16 knees that were revision total knee arthroplasties, 8 had a previous infected total knee arthroplasty, and 17 knees had severe deformities requiring the use of the condylar constrained prosthesis. The patients were rated according to the Knee Society clinical and radiological evaluation protocol. Measurements of femoral and tibial component position were obtained as well as femoral tibial angle, patella position, and cement bone radiolucencies. All clinical measurements were made by an independent physical therapist. Clinical results revealed an improvement from an average preoperative knee score of 38 points to an average postoperative score of 86 points. The clinical results for 19 (58%) knees were excellent, 8 (24%) had a good result, 1 (3%) was fair, 2 (6%) were poor, and 3 (9%) were failures. The patients' average functional levels increased from 24 to 58. The final average flexion was 96 degrees. Three knees have been revised (9%). One was revised for recurrent infection, one for periprosthetic fracture, and one for mechanical loosening of the tibial component. There were no other knees with evidence of radiologic loosening. We conclude that the condylar constrained total knee prosthesis provides an acceptable solution for revision and complex primary total knee replacements at an intermediate follow-up term of 5 years.

The use of femoral intramedullary nailing as an interim or salvage technique during complicated total hip replacementJOURNAL OF ARTHROPLASTYHartford, J. M., Goodman, S. B.1998; 13 (4): 467-472

Abstract

When performing a revision total hip replacement complicated by infection, severe osteolysis, comminuted periprosthetic fracture, and/or extensive bone loss, a single-stage procedure may not be feasible. This study reports four cases of femoral intramedullary nailing as an interim or salvage technique during complicated total hip replacement. This reconstruction provides axial and rotational stability of the femur while maintaining femoral alignment. Furthermore, this reconstruction facilitates early mobilization and rehabilitation of the patient. This interim reconstruction can be converted to a revision total hip replacement at a later time. Alternatively, the stabilized resection arthroplasty may serve as a salvage technique if further reconstruction is not indicated.

Abstract

Clinical pathways are being introduced by hospitals to reduce costs and control unnecessary variation in care. We studied 766 inpatients to measure the impact of a perioperative clinical pathway for patients undergoing knee replacement surgery on hospital costs. One hundred twenty patients underwent knee replacement surgery before the development of a perioperative clinical pathway, and 63 patients underwent knee replacement surgery after pathway implementation. As control groups, we contemporaneously studied 332 patients undergoing radical prostatectomy (no clinical pathway in place for these patients) and 251 patients undergoing hip replacement surgery without a clinical pathway (no clinical pathway and same surgeons as patients having knee replacement surgery). Total hospitalization costs (not charges), excluding professional fees, were computed for all patients. Mean (+/-SD) hospital costs for knee replacement surgery decreased from $21,709 +/- $5985 to $17,618 +/- $3152 after implementation of the clinical pathway. The percent decrease in hospitalization costs was 1.56-fold greater (95% confidence interval 1.02-2.28) in the knee replacement patients than in the radical prostatectomy patients and 2.02-fold greater (95% confidence interval 1.13-5.22) than in the hip replacement patients. If patient outcomes (e.g., patient satisfaction) remain constant with clinical pathways, clinical pathways may be a useful tool for incremental improvements in the cost of perioperative care. Implications: Doctors and nurses can proactively organize and record the elements of hospital care results in a clinical pathway, also known as "care pathways" or "critical pathways." We found that implementing a clinical pathway for patients undergoing knee replacement surgery reduced the hospitalization costs of this surgery.

Abstract

The tissues surrounding 65 cemented and 36 cementless total joint replacements undergoing revision were characterised for cell types by immunohistochemistry and for cytokine expression by in situ hybridisation. We identified three distinct groups of revised implants: loose implants with ballooning radiological osteolysis, loose implants without osteolysis, and well-fixed implants. In the cemented series, osteolysis was associated with increased numbers of macrophages (p = 0.0006), T-lymphocyte subgroups (p = 0.03) and IL-1 (p = 0.02) and IL-6 (p = 0.0001) expression, and in the cementless series with increased numbers of T-lymphocyte subgroups (p = 0.005) and increased TNF alpha expression (p = 0.04). For cemented implants, the histological, histochemical and cytokine profiles of the interface correlated with the clinical and radiological grade of loosening and osteolysis. Our findings suggest that there are different biological mechanisms of loosening and osteolysis for cemented and cementless implants. T-lymphocyte modulation of macrophage function may be an important interaction at prosthetic interfaces.

Abstract

Twenty-nine total hip arthroplasties in 16 patients with juvenile chronic arthritis were performed by one surgeon and followed prospectively. The 9 female and 7 male patients averaged 21 years of age (range, 14-35). Height and weight averaged 160 cm (63 inches) and 53 kg (118 lb.), respectively. Preoperative planning used small or miniature components to accommodate the small anatomic proportions of the hip. The femoral component was cementless in the majority (20/29), but required cementing in 10 of 29 hips because of poor bone stock. The acetabula were reconstructed with a porous-coated cup with or without screws (27/29) or with a cemented cup (2/29). Follow-up periods averaged 53 months (range, 24-100 months). The average Harris hip score improved from 37 to 78 after surgery (P = .0001). Pain relief was excellent; 15 of 16 patients (27/29 hips) expressed a significant improvement in daily function and lifestyle, despite systemic involvement of their arthritis. The range of motion of the hip improved significantly in all planes (P = .001). Two of the 4 uncemented Muller CDH components (Protek, Bern, Switzerland) with a large offset have migrated into varus; both are pain-free. One cemented femoral component has been revised because of aseptic loosening. The use of a small or miniature, cemented or cementless femoral component and a porous-coated cup appears to provide an excellent method of hip reconstruction for patients with juvenile chronic arthritis and small anatomic proportions; however, a femoral component with too great an offset should be avoided, because this may result in varus migration of the stem.

Abstract

Bone quality, initial fracture displacement, severity of fracture comminution, accuracy of fracture reduction, and the placement of the internal fixation device are important factors that affect fixation stability. New high strength cements that are susceptible to remodeling and replacement for fracture fixation may lead to improved clinical outcome in the treatment of hip fractures. Norian SRS is an injectable, fast setting cement that cures in vivo to form an osteoconductive carbonated apatite of high compressive strength (55 MPa) with chemical and physical characteristics similar to the mineral phase of bone. It can be used as a space filling internal fixation device to facilitate the geometric reconstruction, load transfer, and healing of bone with defects and/or fractures in regions of cancellous bone. Furthermore, this cement can improve the mechanical holding strength of conventional fixation devices. Use of this material potentially could improve fracture stability, retain anatomy during fracture healing and improve hip function, thus achieving better clinical outcomes. In vivo animal studies have shown the material's biocompatibility, and cadaveric studies have shown the biomechanical advantage of its use in hip fractures. Initial clinical experience (in 52 femoral neck fractures and 39 intertrochanteric fractures) showed the potential clinical use of this innovative cement in the treatment of hip fractures.

Abstract

We performed preoperative and postoperative duplex ultrasonography examinations on both lower extremities in 128 patients undergoing 146 hip and knee reconstructive procedures. The results of the examinations were reviewed by an independent radiologist who specializes in these studies. Three of the 128 patients (146 procedures; 2.1%) had evidence of a deep venous thrombosis or other venous abnormality before surgery. Three additional patients developed a deep venous thrombosis after surgery, despite mechanical and pharmacologic prophylaxis. We have discontinued performing preoperative duplex ultrasonography prior to primary, uncomplicated total joint replacement of the lower extremities. We continue to perform duplex ultrasonography before surgery in patients at high risk, with a history of deep venous thrombosis or phlebitic syndrome, and in those who have previously had major surgery on the lower extremities.

Abstract

An investigation was performed to study the mechanical performance of fiber-reinforced composite hip prostheses. In Part I of the study, a three-dimensional finite element code was developed for analyzing a composite hip prosthesis in a femur. The material properties of the composite were treated as anisotropic and inhomogeneous while the properties of the femoral bone were treated as anisotropic and homogeneous. All the materials were assumed to behave linear-elastically. Thermoplastic graphite/PEEK material was selected for the study. No slippage was assumed at the interface between the implant and the surrounding femoral bone. In Part II, numerical simulations were performed using the code to study the performance of a composite prosthesis in the femur. The stress/strain distributions, micromotions, and strain energy density of the surrounding femoral bone were evaluated and found to be related to initial fixation and long-term stability of the prosthesis in the femur. Numerous fiber orientations were studied, and the results of the calculations were compared with those generated from a prosthesis made of cobalt chrome and Ti-6Al-4V titanium alloys. Based on the analysis, it was shown that compared to conventional metallic implants more favorable stresses and deformations could be generated in the femur using composite implants. In addition, by changing fiber orientations according to femoral loads, a composite implant could be designed specifically for the left or the right femur.

Abstract

A new biomechanical model of single-limb stance was developed to test the stability of intact, injured, and internally fixed pelves.Single-limb stance was simulated by applying muscle forces and body mass loading to cadaver pelves. We created a rotationally unstable "open-book" pelvic injury in nine embalmed pelves by dividing the ligaments of the pubic symphysis, pelvic floor, and anterior and interosseus sacroiliac joint. All pelves were devoid of gross structural abnormalities.Two methods of internal fixation of the pubis symphysis were compared: (a) a curved six-hole 3.5-millimeter reconstruction plate across the superior pubic symphysis, and (b) the same six-hole 3.5-millimeter reconstruction plate plus a perpendicularly oriented four-hole 3.5-millimeter reconstruction plate placed across the anterior symphysis.We measured vertical shear displacement at the public symphysis and horizontal displacement at the anterior sacroiliac joint. The results for the injured and fixed specimens were compared with each other and with the results for the intact specimens.The injured unfixed specimens showed marked instability that was prevented by both methods of fixation of the pubic symphysis. No significant differences could be demonstrated between single and double plating of the disrupted pubic symphysis when using this single-limb stance model.This model of single-limb stance suggests that a single symphyseal plate across the pubic symphysis can stabilize the open-book injury under short-term quasi-static loads.

Abstract

Few guidelines are currently available to the surgeon when choosing a specific femoral component for cementless total hip replacement (THR). A survey of the members of the American Association for Hip and Knee Surgeons (AAHKS) was conducted to gain insight into the importance of implant material, stress shielding, and micromotion in the selection of cementless femoral components. A comprehensive survey was distributed to 300 orthopedic surgeons selected from the members of the AAHKS; 169 of the 300 surgeons completed the detailed questionnaire. The results of the survey were analyzed using the SPSS software package to obtain general trends in opinion, and a stepwise regression analysis was used to correlate responses with training and clinical experience. Interestingly, there was little consensus among surgeons with respect to the relative importance of implant material, stress shielding, and micromotion in the selection of prostheses for cementless THR. In general, bone loss secondary to stress shielding was the least important issue, and axial and rotational micromotion were considered progressively more significant problems. Cementless titanium alloy stems were perceived as offering no significant advantage over cobalt chrome alloy stems. Moreover, there was no consensus as to whether a collar was advantageous. Prosthesis stability, restoration of motion, and a proven clinical record were more important to surgeons than were ease of implantation and removal, cost, and availability.

Abstract

The purpose of this study was to characterize the cell types (using immunohistochemistry) and cytokine expression (using in situ hybridization) of tissues surrounding well fixed and loose cemented prostheses undergoing revision. Clinical and radiographic data were gathered prospectively for a series of cemented total joint replacements undergoing revision. Three groups were identified: (1) loose implants with osteolysis (10 specimens), (2) loose implants without osteolysis (11 specimens), and (3) well fixed implants (7 specimens). At surgery, a specimen was harvested from the bone cement interface. Immunohistochemical staining was performed using monoclonal antibodies to identify macrophages and lymphocyte subgroups. Human antisense probes were selected to identify the mRNA for specific cytokines using in situ hybridization. The percentage of positively staining cells was determined for each antibody or probe using a grid counting technique. Tissues from loose cemented prostheses with osteolysis contained significantly greater numbers of macrophages and T lymphocytes compared with tissues from loose and well fixed cemented prostheses without osteolysis. The number of interleukin-1 and interleukin-6 positive cells was highest in specimens with osteolysis and lowest in specimens from well fixed prostheses. These cytokines modulate the growth and differentiation of cells in the immune system and the monocyte and macrophage system and mediate the remodeling of bone and mesenchymal tissues. Specific cell populations and cytokine profiles appear to be involved in periprosthetic osteolysis; this information may be useful in planning strategies for prevention and treatment.

Abstract

Particles similar to those generated from joint replacements affect net bone formation within the Bone Harvest Chamber in rabbits. Whether these effects depend on the concentration of particulate materials is unknown. In this study, we performed a histomorphologic and morphometric analysis of net bone formation in the Bone Harvest Chamber in the presence of different concentrations of phagocytosable particles of high density polyethylene and titanium 6-aluminum 4-vanadium alloy. Chambers were implanted in 9 mature New Zealand white rabbits bilaterally. Concentrations of 10(6), 10(7) and 10(8) polyethylene particles/mL, and 10(8) and 10(9) particles/ mL of titanium alloy in 1% sodium hyaluronate carrier were implanted for 3-week periods in sequence in each of the chambers. 3-week control periods in which nothing was implanted in the chamber were included between the treatments. Increasing concentrations of polyethylene particles were associated with a more marked foreign body response and fibrosis. Net bone formation for the three polyethylene doses was reduced by 11%, 21% and 33% of controls, respectively. For titanium alloy, net bone formation was reduced by 8% and 56% of controls, for concentrations of 10(8) and 10(9) particles/mL, respectively. Our findings suggest possible adverse effects of wear debris on net bone formation and bony remodeling in the prosthetic bed, when concentrations of specific particles reach critical local levels.

Abstract

The pneumatic tourniquet produces ischemic changes in limbs. The effects of tourniquet release on systemic blood pressure and metabolic parameters were studied in 11 adult patients undergoing total knee replacement under general anesthesia. Mean arterial pressure (MAP) decreased rapidly after the release of the tourniquet, becoming significant at 3 min and remaining significantly depressed up to 15 min post release. Arterial pH, PaO2, PaCO2, lactate acid, and potassium changed significantly after the release, but normalized within 30 min. These results are notably different from a previous study in a similar patient population undergoing knee replacement under epidural anesthesia. Compared to patients under epidural anesthesia, patients receiving general anesthesia with mechanical ventilation are unable to compensate for the metabolic load caused by the tourniquet release, as the latter group are unable to alter their ventilatory rate. In elderly patients with decreased cardio-pulmonary reserve, this may be of clinical importance.

Abstract

A consecutive series of 49 patients who had a primary total hip arthroplasty (THA) for osteoarthritis is reviewed to determine the difference in clinical outcome between the direct lateral and the posterior surgical approaches to the hip. Group 1 comprised 28 patients off had THA by the same surgeon using a posterolateral approach. Group 2 comprised 21 patients who had THA using the direct lateral approach, modified from Hardinge. The improvement in the limp, abductor strength, Trendelenburg test, and range of motion over time was similar in the two groups. The average Harris hip score at 1 year was 90 for Group 1 (posterior approach) and Group 2 (lateral approach). At 2-year minimum follow up, the Harris hip score was 94 for both groups. Radiographic review showed that the incidence and severity of heterotopic bone was also similar for both groups. The authors conclude that the clinical and radiographic outcome for THA using the posterior and the lateral approaches to the hip yield similar clinical results.

Abstract

Previously, small phagocytosable particles of high density polyethylene (HDPE) but not Ti6-Al4-V alloy, at a concentration of 10(8) particles/mL inhibited net bone formation in vivo after 3 weeks in the bone harvest chamber (BHC). These findings reflected the effects of particles during the phase of bone ingrowth. In this study, we tested whether these effects persisted or were different during the phase of bone maturation and remodeling. BHCs were bilaterally implanted in mature male NZW rabbits. After a 6-week period for osseointegration, the contents of the chamber were harvested and discarded. One percent sodium hyaluronate, the carrier, was then placed within the canal of the chambers bilaterally and the tissue within the chambers was harvested 3 weeks later. HDPE particles were then inserted unilaterally for a 3-week period, followed by Ti6-Al4-V for 3 weeks, HDPE for 6 weeks, and Ti6-Al4-V for 6 weeks. The side chosen for each treatment was switched consecutively; the nonimplanted, contralateral chamber served as a control. At 3 weeks the control treatments yielded trabeculae of woven bone in a fibrovascular stroma. By 6 weeks, the peripheral trabeculae were thicker, and a central marrow cavity was developing. Bone ingrowth was less with HDPE particles at 3 and 6 weeks compared to controls. Ti6-Al4-V particles did not inhibit bone ingrowth at 3 weeks but showed a trend at 6 weeks. The characteristics of particles affect the differentiation, maturation, and remodeling of mesenchymal tissue differently.

Abstract

Wear debris has been implicated in the pathogenesis of loosening and osteolysis of total joint replacements by stimulating a foreign body and chronic inflammatory reaction capable of bone resorption. Whether increasing concentrations of wear particles have an adverse biological effect on bone has not been elucidated. We performed a histomorphological and semi-quantitative morphometric analysis of the reaction of bone to different concentrations of phagocytosable particles of high-density polyethylene (HDPE) and titanium 6-aluminium 4-vanadium alloy (Ti-6Al-4V) implanted in the rabbit tibia. The Ti-6Al-4V particles had a diameter of 4.0 +/- 4.4 microns (mean +/- SD); the HDPE particles averaged 4.7 +/- 2.1 microns. Suspensions of 10(6)-10(9) particles per ml were mixed in saline, sterilized, and introduced through a drill hole into the proximal tibia of 30 mature female rabbits. Controls included drilled, but non-implantable limbs. The animals were killed at 16 weeks and histological sections were made of the implant area. Histomorphological assessment was carried out using an interactive image analysis system. The parameters assessed included the presence of histiocytes, foreign body giant cells and inflammatory cells, the location and number of particles, the presence of haematopoeitic elements, fat or necrosis of the marrow, whether healing of the cortical window had taken place, and whether there was evidence of formation or resorption of bone by the periosteum, cortex and marrow. A semi-quantitative rating system was employed. Phagocytosable particles of Ti-6Al-4V and HDPE, in concentrations of 10(6)-10(9) particles per ml, evoked a histiocytic reaction without extensive fibrosis, necrosis or granuloma formation. This reaction occurred without disturbing the normal repair processes of bone formation and resorption to the surgical insult. A clear dose-response effect on the histological parameters assessed in this study was not noted. Using the present model, by 16 weeks, a similar "one time' particle load could be accommodated. The ongoing generation of particulate debris over a more extended period of time might be necessary before the remodelling processes of bone would be disturbed.

Abstract

Previous studies have attempted to define the biologic properties of the bone-implant interface using a single specimen harvested from the periprosthetic tissues. The purpose of this study was to examine the heterogeneity in cellular and cytokine profiles of multiple samples taken from the tissues surrounding revised hip prostheses. Clinical and radiographic data for nine patients undergoing surgical revision was gathered prospectively. Three tissue samples were taken systematically from the acetabular and/or femoral bed. Morphologic characteristics of the tissues were assessed using hematoxylin and eosin-stained sections. Immunohistochemical staining was performed using monoclonal antibodies to identify macrophages (EMB11 and CD68); activated macrophages (Leu M3); total T lymphocytes (Leu 4 and T11); T-helper lymphocytes (Leu 3A and CD4); cytotoxic/suppressor T lymphocytes (Leu 2A and CD3); and fibroblasts (5B5). In situ hybridization was used to identify the mRNA for specific proteins: interleukin (IL)1 alpha and -beta, IL-2, IL-6, transforming growth factor beta, tumor necrosis factor alpha (TNF alpha), platelet-derived growth factor alpha (PDGF alpha), and interferon gamma. A quantitative assessment was performed for each section by calculating the percentage of positively staining cells using a light microscope and grid-counting technique. A random effect analysis of variance was calculated to determine both the variance between samples within each patient and the variance between different patients. Standard deviations contributed by sampling variance and patient variance were calculated and an F test was applied. Tissue samples taken from different regions of the bone-prosthesis interface showed marked heterogeneity in cellular and cytokine profiles. Critical F values indicating a statistically significant degree of variance between different tissue samples were exceeded for macrophages, cytotoxic/suppressor T lymphocytes, and T-helper lymphocytes. The cytokine profile was significantly different for IL-2, PDGF alpha, and TNF alpha. This tissue heterogeneity may be due to different mechanical and biologic environments along the bone-prosthesis interface. Thus, caution must be exercised in defining the biologic properties of the tissue surrounding revised prostheses according to a single biopsy.

Abstract

Early reduction and rigid fixation of unstable vertical shear pelvic fractures has been shown to decrease the incidence of late sequelae and facilitate early mobilization. The results of fixation of the posterior pelvic ring without anterior fixation are unknown. The purpose of this study was to perform a biomechanical comparison of the most frequently used techniques of posterior fixation for unstable pelvic sacroiliac dislocations in conjunction with ipsilateral rami fractures, i.e., an unstable vertical shear injury. The four methods of posterior fixation tested included sacroiliac (SI) screws, anterior SI plates, transiliac bars, and a combination of SI screws and transiliac bars. Six cadaveric pelvises were tested in axial compression and torsion on a biaxial servohydraulic testing machine. Compared to the intact pelvis, single posterior methods of fixation provided approximately 70-85% resistance to axial and torsional loading. By combining SI screws with transiliac bars, approximately 90% of intact pelvic stability was achieved. Our results suggest that rigid posterior fixation of sacroiliac dislocations alone may obviate the need for additional complex anterior surgical procedures to fix rami fractures.

Does the immune system play a role in loosening and osteolysis of total joint replacements?JOURNAL OF LONG-TERM EFFECTS OF MEDICAL IMPLANTSGoodman, S. B.1996; 6 (2): 91-101

Abstract

Total joint replacement is a highly successful surgical procedure with an excellent outcome over many years. However, because this procedure is now being performed in younger patients, and because the average age of our population continues to increase, greater expectations have been placed on joint implants in the hope that they will last forever. Aseptic loosening and osteolysis of total joint replacements are the main processes limiting long-term implant survival. This paper focuses on the possible role of immunological mechanisms in the processes of loosening and osteolysis of joint replacements, with special emphasis on polymeric materials. This topic is very controversial: In vitro experiments and in vivo studies in animals and humans are reviewed and provide evidence for both sides of the debate. In some patients, immunological processes appear to be activated after a total joint replacement has been implanted. Specific materials or their by-products might function as haptens and elicit a T-lymphocyte-mediated, delayed hypersensitivity reaction. Many factors probably are important, including the genetic makeup and immune competence of the patient, prior exposure to the same or similar materials, degree of exposure (rate of generation of particles and the efficacy of clearance mechanisms), and characteristics of the particles themselves.

Abstract

We performed a histomorphological and morphometric analysis of the effects of short daily periods of micromotion and phagocytosable particles of high density polyethylene (PE) on bone ingrowth into a 1 x 1 x 5 mm canal within a titanium chamber in rabbits. The micromotion chamber (MC) was implanted in the tibia of nine mature New Zealand white rabbits. After osseointegration and first harvest of tissue, 40 micromotions (amplitude = 0.5 mm) were applied daily at a rate of 1 Hz for a 3-week period. The tissue within the chamber was then harvested. For the second treatment, PE particles (10(8)/mL) were placed within the canal. The tissue in the chamber was harvested 3 weeks later. The next treatment was a 3-week rest period, in which neither micromotion nor particles were utilized; a harvest followed. The final treatment combined PE particles and micromotion, followed by a harvest 3 weeks later. Sections from control harvests contained extensive trabecular bone arranged longitudinally throughout the canal in a fibrovascular stroma. Micromotion produced longitudinally oriented fibrous tissue within the chamber. PE particles were associated with macrophages, surrounding and engulfing the birefringent particles. The combination of particles and micromotion produced a fibrous stroma laden with macrophages. PE particles and micromotion, alone or together, produced a similar effect in inhibiting bone ingrowth, compared to nonmoved chambers without particles. In this short-term experiment, no additive or potentiating effect of these two stimuli could be demonstrated.

Abstract

Particulate wear debris from joint replacements has been implicated in the etiology of periprosthetic bone resorption. However, the effect of high-density-polyethylene or cobalt-chromium-alloy particles on osteoclastic bone resorption in vivo has not been studied previously, to our knowledge. Therefore, we examined the effect of these particles on tissue ingrowth, net bone formation (per cent trabecular bone), and osteoclastic bone resorption (osteoclasts per unit of bone surface) with use of a bone-harvest chamber that had a transverse one-millimeter channel for tissue ingrowth. After an initial six-week period for incorporation of the chamber into the proximal part of the tibia of rabbits, the contents of the channel were harvested repeatedly at three-week intervals. The carrier solution, 1 per cent sodium hyaluronate, was implanted first. In subsequent implantations, the hyaluronate was mixed with high-density-polyethylene or cobalt-chromium particles at concentrations of 10(8) particles per milliliter. The tissue harvested from the chambers that contained no particles was composed of longitudinally oriented trabecular bone in a fibrovascular stroma. Particulate high-density polyethylene evoked a moderate foreign-body reaction and a chronic inflammatory response and decreased net bone formation. When cobalt-chromium particles had been implanted, the tissue exhibited a more florid foreign-body reaction and a chronic inflammatory response, often in a nodular arrangement, in a background of dense connective tissue. Bone was sparse, and areas of cell necrosis and hyaline degeneration were noted. Histomorphometric analyses were carried out to determine the amount of net bone formation and osteoclastic bone resorption in the presence or absence of high-density-polyethylene or cobalt-chromium particles. The amount of bone was greatest in the control specimens, moderately decreased in the presence of high-density-polyethylene particles, and greatly decreased in the presence of cobalt-chromium particles. The number of osteoclasts in Howship lacunae per unit of trabecular bone surface was increased in the presence of high-density polyethylene, indicating that these particles stimulate osteoclastic bone resorption.

Abstract

The purpose of this study was to determine whether small, phagocytosable particles of titanium alloy (Ti) and high-density polyethylene (HDPE) have an adverse effect on bone ingrowth. The bone harvest chamber (BHC) was implanted bilaterally in the proximal tibial metaphysis of six mature rabbits. The BHC has a transverse 1-mm wide pore providing a continuous canal through the chamber for tissue ingrowth. After an initial 6-week period for osseointegration of the BHC, the contents of the canal were harvested repeatedly at 3 weekly intervals. This could be done with the chamber in place, without disturbing its exterior surface or the surrounding bone. The carrier solution, 1% sodium hyaluronate (Healon) was implanted first. In subsequent implantations, Healon was mixed with particles of HDPE or Ti averaging 4.7 +/- 2.1 and 3.0 +/- 2.6 microns, respectively. The contralateral chamber was left empty and served as a control. The chambers were harvested repeatedly, alternating experimental and control sides. The sections from the control side, and those containing Healon alone demonstrated extensive trabecular bone in a fibrovascular stroma. The sections containing Ti alloy particles were qualitatively and quantitatively similar to the control sections and those containing Healon, except for the presence of small black granules of Ti alloy, dispersed in the fibrovascular stroma or phagocytosed by scattered macrophages. The sections containing HDPE particles were infiltrated and engulfed by mononuclear and multinuclear histiocytic cells in a highly fibrous stroma. The majority of the multinucleated cells present were interpreted as being foreign body giant cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A clinical and radiographic study of the "safe area" using the direct lateral approach for total hip arthroplasty.journal of arthroplastyComstock, C., Imrie, S., Goodman, S. B.1994; 9 (5): 527-531

Abstract

The purpose of this clinical and radiographic study is to determine whether the surgeon can remain within the 5 cm "safe zone" while using the direct lateral approach during total hip arthroplasty (THA) without endangering the superior gluteal nerve. The direct lateral approach was used in a prospective, consecutive series of 36 primary THAs in 31 patients performed by one surgeon. At the time of closure of the abductor muscle layer, a small metallic clip was placed at the superior extent of the incision into the gluteus medius. After surgery, the patients were mobilized on crutches with protected weight bearing for either a 6-week (hybrid THA) or 12-week (uncemented THA) period. Before surgery, and at 3, 6, and 12 months after surgery, abductor strength and the Trendelenburg sign were measured by the same physical therapist. The vertical distance from the superior pole of the greater trochanter to the base of the clip was measured on all radiographs of the pelvis and corrected for magnification. Before surgery, only 25 of the 36 hips demonstrated abduction strength of 4/5 or greater. Three months after surgery, 34 hips had a grade of 4/5 or greater for abductor strength. The Trendelenburg sign was positive in 24 of 34 hips before surgery, in 5 hips at 3 months, in 1 hip at 6 months, but negative in all hips by 12 months. The clip was located 3.2 +/- 1.3 cm (mean +/- SD) vertically from the superior pole of the greater trochanter. In 34 of 36 hips (95%), the 5 cm safe zone was respected.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Short, daily periods of externally-applied strain have been shown previously to affect the differentiation of mesenchymal tissue. In this study, we examine the effects of discontinuing a strain protocol known to produce primarily fibrous tissue rather than bone in the micromotion chamber (MC). Five MCs were inserted into the proximal tibial metaphysis of mature male New Zealand white rabbits. The MC has a 1 x 1 x 5 mm pore for tissue ingrowth. After osseointegration of the fixed outer cylinder of the chamber, the inner movable core was manipulated for 40 cycles per day delivered at a rate of 1 Hertz ('40'). This provided motion at the interface between the cylinder and the core. The tissue in the pore was harvested after 3 wks. The MCs were then manipulated at 40 cycles per day for 3 wks and then the manipulations were discontinued for 3 additional wks ('40 + 0'); the contents of the chamber were harvested after 6 wks. Finally, the chambers were left without manipulation ('0') and harvested after 3 wks. Histological sections from unmoved chambers ('0') contained extensive trabecular bone, embedded in a fibrovascular stroma. The '40' specimens were composed primarily of longitudinally orientated fibrous tissue. The '40 + 0' specimens were similar histologically to the '0' specimens. The amount of bone ingrowth expressed as a percentage of the area of the section averaged 37 +/- 6 (mean +/- standard error of the mean) for the '0' specimens, 20 +/- 2 for the '40' specimens and 37 +/- 7 for the '40 + 0' specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Five femora (four cadaveric and one plastic) were used to measure the intramedullary pressures simultaneously at two different locations along the proximal femur during the insertion of bone cement and the femoral component using modern cement technique. The pressures were monitored by transducers located at the midpoint of each femoral stem (P1), and just beyond the tip of the femoral stem proximal to a cement plug (P2). Transient increases in intramedullary pressure were noted during the initial compaction of the bone cement using a conventional device. However, during insertion of the femoral component, the pressures at P1 and P2 increased dramatically to peak pressures exceeding 2385 mm Hg at P1 and 3710 mm Hg at P2 respectively. These pressure elevations were not sustained; eight to 10 minutes after prosthesis insertion, the pressures decreased to below baseline levels in all five femora. This probably resulted from contraction of the cement during the curing phase. Transient elevations of intramedullary pressure to levels greater than 100 times capillary pressure are produced during hip replacement using modern cement technique. The highest pressures are generated during insertion of the femoral component rather than during the cement compaction step. These findings suggest that the use of a cement compactor to improve intrusion of the cement into bone is probably unnecessary.

Abstract

We examined the effect of methylmethacrylate cement on venous embolization and cardiac function in 20 patients having total hip arthroplasty under general anesthesia. Segmental wall motion abnormalities and intracardiac targets (presumably emboli) were investigated by making videotaped recordings of the transgastric short axis and longitudinal 4-chamber views of the heart with transesophageal echocardiography at different points during surgery. The incidence of segmental wall motion abnormalities was the most frequent during insertion of cemented femoral prostheses (8 of 14 patients had wall motion abnormalities). This was significantly different from baseline measurements taken at the beginning of surgery (P < 0.05). In addition, there were also significantly more segmental wall motion abnormalities in patients having a cemented femoral component compared to those having an uncemented femoral prosthesis (P < 0.05). The incidence of wall motion abnormalities during acetabular and femoral reaming and during wound closure was not significantly different from baseline. Intracardiac targets (emboli) were seen in all 20 patients during surgery. The largest number of emboli occurred during reaming of the femur and during insertion of the femoral prosthesis. Significantly more emboli were seen with cemented components (P < 0.02). Most emboli were small (< 2 mm) and appeared similar to the microbubbles produced by agitating saline with a small amount of air. Six patients also had larger (> 5 mm) emboli that appeared to be solid material. One patent foramen ovale was detected (5% incidence). There were no adverse cardiac or neurologic events, and heart rate and arterial blood pressure remained within normal limits throughout surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Fourteen mature New Zealand white female rabbits had a right, cemented, tibial hemiarthroplasty using a stemmed, fluted, titanium alloy, condylar-type prosthesis. In one group (seven rabbits), polymethyl methacrylate (PMMA) was used to cement the prosthesis firmly. In a second group (seven rabbits), the prosthesis was treated with cement ex vivo; the prosthesis and cured cement were then implanted, and rotated once within the bone to ensure that the prosthesis was loose fitting. Roentgenograms performed postoperatively and at 3 months were graded for new (i.e., not present on the immediate postoperative radiograph) radiolucent lines. At 3 months, the tissue adjacent to the implant was harvested sterilely and cultured over a 3-day period; the tissues and culture supernatants were then assayed for total protein, DNA content, and lysosomal enzyme activity (N-acetyl-beta-D-glucosaminidase and beta-glucuronidase). The mean cumulative grading of new lucent lines was 0.4 +/- 0.3 (mean +/- standard error) for the well-fixed prosthetic group and 2.0 +/- 0.6 for the loose prosthetic group. The tissue surrounding loose prostheses contained more DNA and total protein, and produced greater amounts of lysosomal enzymes compared to well-fixed prostheses. The control left sides were not statistically different for any parameter analyzed. The increased DNA content demonstrates an increase in cellularity of the tissue surrounding loose prostheses. Normalization of the relative amount of enzyme released as a function of cellularity (DNA) suggests that the influx of cells into the area surrounding loose prostheses may be more important to the overall increase in lysosomal enzyme release than increased production of lysosomal enzymes by individual cells.

Abstract

The interfacial membrane harvested from failed joint replacements contains particulate debris from the materials used for the implant. To define the tissue response to particulate titanium alloy and hydroxyapatite (HA) alone, 16 mature New Zealand white rabbits were divided into 2 groups of 8 rabbits. Using sterile technique, a drill hole was placed anteromedially in the tibia, 1 cm distal to the knee joint bilaterally. The marrow was scooped out and 0.25 mg of either titanium alloy particles or HA particles were inserted in the right tibia. The titanium alloy particles had a diameter averaging 4.0 +/- 4.4 microns (mean +/- standard deviation) and an aspect ratio (the ratio of the maximum length divided by the maximum width) of 1.84. The HA particles had a diameter of 4.4 +/- 3.3 microns and an aspect ratio of 1.76. The left leg was prepared in a similar fashion, but no biomaterial was implanted. The animals were killed after 16 wk. The harvested tibiae were processed with decalcification and the plastic-embedded sections were subjected to histomorphological analysis. Black titanium alloy particles were present within the bone marrow fat between haematopoietic cells, and within scattered macrophages. The surrounding bone appeared to be unaffected. Within the spongiosa, the HA particles were surrounded by small numbers of mononuclear histiocytes or encased within a shell of new appositional bone. Where HA deposits were exposed to the endosteal aspect of bone, there was scalloping of the surface of the HA in a pattern suggestive of resorption or dissolution of the HA particles.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

In 1892, J.L. Wolff believed that bone was a dynamic organ that responded to the biomechanical environment. Research has shown that mechanical stimulation can have a profound effect on the differentiation and development of mesenchymal tissues. It would appear that a 'window' of mechanical strain exists which may facilitate or discourage the accretion of bone. With respect to processes such as fracture healing and ingrowth of bone into porous coated prostheses, it may be possible to modulate the mechanical environment with the application of well-defined, exogenous loads in order to promote a more favourable outcome.

Abstract

Fourteen mature New Zealand white female rabbits had a unilateral cemented, stemmed, titanium, condylar-type tibial hemiarthroplasty, using an anteromedial arthrotomy of the right knee. The articular cartilage and minimal bone were resected. There were two prosthetic groups of seven animals each: a well-fixed, non-loose group and a loose group. In the non-loose group, the implant was inserted into the cement bed and axially compressed until the PMMA had cured. In the loose group, the same volume of cement was allowed to cure on the implant ex vivo; the prosthesis was then implanted to ensure that it was loose fitting. Radiographs were performed at zero and 3 months and graded for new lucent lines. Histological analysis was performed using undecalcified coronal sections, surface stained with toluidine blue with the prosthesis in situ, and the cement mantle preserved. Back-scattered electron microscopy was also performed. The mean cumulative grading of new lucent lines was 0.3 +/- 0.1 for the non-loose group and 2.2 +/- 0.4 for the loose group (P < 0.005). Non-loose prostheses were surrounded by a thin fibrous membrane or bone. Loose prostheses were surrounded by a thicker, fibrous tissue layer, containing histiocytes and giant cells which were more prevalent around cement particles, especially near the prosthetic tip. These findings parallel the histology found at cemented prosthetic interfaces in humans. The results of this study suggest that the fibrohistiocytic membrane commonly found around loose cemented implants may be the result of, rather than the cause of, the loosening process.

Abstract

This study examines the accretion rate of bone surrounding orthopaedic polymeric implants in different physical forms. Forty mature, female, New Zealand white rabbits were used in the study. Bilateral 6mm drill holes were made in the anteromedial tibias, 1cm from the joint line. The right tibia received a polymeric implant and the left tibia functioned as a prepared but nonimplanted control. The animals were allocated as follows: Group 1--bulk, preformed cooled polymethylmethacrylate (PMMA) plug; Group 2--bulk, doughy PMMA implant; Group 3--cement polymer powder; Group 4--bulk ultra-high-molecular-weight polyethylene (UHMWP) plug; Group 5--UHMWP particles averaging 67.29 mum; Group 6--UHMWP particles averaging 15.68 mum. All animals received the same volume of PMMA or UHMWP. The animals were killed after four months by barbiturate overdose. Beginning four weeks prior to sacrifice, the animals were given tetracycline injections at two-weekly intervals for two consecutive days. The upper tibias were harvested bilaterally and the specimens were processed undecalcified. Using a fluorescent microscope, the distance between successive tetracycline bands was assessed. Doughy PMMA tended to suppress bone formation compared to the control side, whereas preformed PMMA plugs and particulate PMMA polymer did not. This may be due to the heat of polymerization or to the presence of residual monomer in the doughy group. Polyethylene tended to facilitate bone accretion whether in bulk or particulate form when compared to the control side or to doughy cement. This effect was less marked when the cement was in particulate form.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

To our knowledge there have been no reports of late rupture of the posterior cruciate ligament (PCL) as a cause of instability in PCL-retaining total knee prostheses. In our experience of 150 total knee replacements using PCL-retaining prosthesis, three cases (2.0%) of late rupture of the posterior cruciate ligament have occurred, each leading to chronic instability, disabling pain, and revision arthroplasty. In each case rupture of the posterior cruciate ligament was confirmed at the time of revision arthroplasty. The use of a more constrained prosthesis led to a successful outcome in each case.

Abstract

Sixteen mature New Zealand female rabbits had cemented, tibial hemiarthroplasty of the right knee (correction of hip) using a stemmed, fluted, titanium-alloyed, condylar type prosthesis. In the fixated prosthetic group (eight rabbits), a 1.5-cm3 doughy bolus of polymethylmethacrylate (PMMA) was used to cement the prosthesis firmly. In the loose group (eight rabbits), the cement was allowed to cure ex vivo on the implant; the prosthesis was then implanted and rotated to ensure that it was loose fitting. Roentgenograms performed postoperatively and at three months were graded for new lucent lines. The implant area was harvested aseptically and cultured during a three-day period, and the cumulative collection of tissue culture supernatants was assayed for prostaglandin E2 (PGE2). The mean cumulative grading of new lucent lines was 0.4 +/- 0.2 (mean +/- SEM) for the fixated prosthetic group and 2.3 +/- 0.5 for the loose prosthetic group. Specimens from the nonloose group produced 8.85 +/- 1.44 ng of PGE2 on the right prosthetic side, and 17.29 +/- 3.72 ng of PGE2 on the left, nonimplanted side. Specimens from the loose prosthesis group produced 52.35 +/- 16.28 ng of PGE2 on the right prosthetic side and 17.29 +/- 3.72 ng of PGE2 on the left, nonimplanted side. Increased PGE2 production relative to fixated prostheses was noted in the membranes surrounding loose prostheses. The left, nonimplanted sides were not statistically different. Roentgenographic and biochemical evidence indicates that a cemented tibial hemiarthroplasty implanted in the rabbit knee can provide a short-term model of arthroplasty loosening.

Abstract

The method and results of preoperative templating for the re-establishment of leg length equality during total hip replacement (THR) are reported. The method is a modification of the technique of Müller and requires an anteroposterior radiograph of the pelvis that includes the proximal third of both femora, appropriate acetabular and femoral templates, and tracing paper. To obtain equalization of leg lengths and tissue tension, a composite drawing is made of the operative plan, with all component sizes and important measurements clearly marked. During THR, the lesser trochanter is identified and the femoral neck is osteotomized after a direct measurement is made. These principles were followed in a prospective, consecutive series of 42 primary THR procedures performed by one surgeon. All the radiographic measurements were performed by a single observer. The leg length discrepancy on the postoperative radiograph averaged 3mm (standard deviation = 3mm, range: -9 to +9mm). The postoperative clinical leg length discrepancy averaged 0mm (range: -10 to +10mm). None of the patients complained of leg length inequality. Preoperative templating allows different alternatives to be traced on paper prior to the actual surgical procedure. This method also helps determine the requirements for special prosthetic implants. Acceptable results for postoperative leg length equality may be reliably achieved using this method.

Abstract

In this study, accurate identification of the location of the acetabular teardrop and ilioischial line on the cadaveric pelvis was attempted using computerized tomographic (CT) scanning and conventional roentgenographic techniques. The acetabular teardrops and ilioischial lines of four whole pelvic anatomic specimens were outlined with barium impregnated latex strings utilizing conventional roentgenograms, fluoroscopy, and stereoscopic control. Computed tomographic scanning was then performed, and axial and coronal CT reformations were created. Roentgenograms, CT scans, and magnetic resonance images of the pelves of ten patients with avascular necrosis of the femoral head were also reviewed to correlate the cadaveric study with specific clinical cases. The acetabular teardrop is a U-shaped figure on roentgenograms taken in a neutral anteroposterior projection. It is a complex geometric structure found to be in a constant position in the anteroinferior aspect of the acetabular wall. Its appearance changes with rotation of the pelvis or incident beam, as the teardrop represents a two-dimensional image of the tangents of a series of curves of varying radii. The ilioischial line is located posterior to the acetabulum and corresponds to tangents on the cortex of the posterior column. Computed tomography imaging with reconstruction identifies acetabular anatomy most clearly and allows precise measurements to be made.

Abstract

A model of an unstable femoral neck fracture was used in this study to compare the axial and torsional displacement obtained when the neck was fixed by a compression hip screw (CHS) and side plate, or three Knowles pins. Six paired, embalmed femora were mounted on a special, custom-made jig that grasped the femoral head and shaft securely. A standardized osteotomy was made with an oscillating saw, bisecting the distance between the lower cartilaginous portion of the femoral head and the intertrochanteric line. A 5-mm thick slice of bone was excised from the posteromedial quadrant of the distal fragment. The right or left femur in each pair was then randomly assigned to internal fixation with either three Knowles pins or a keyed CHS plus a 130 degrees four-hole side plate. After potting of the specimens and application of rosette strain gauges, axial displacements were measured during the application of in-plane and out-of-plane compressive loads. The resistance to torsion was also determined. There were no statistical differences between the two devices for compressive or torsional loading using this model.

Abstract

The micromotion chamber for implantation in the rabbit tibia consists of two titanium components that have a 1 mm contiguous pore for bone ingrowth. The fixed, outer cylinder of the chamber contains a movable inner core that can be manually rotated. The model is unique because specific, discrete, daily periods of motion of a predetermined amplitude and frequency can be delivered to the ingrowing tissue. In the present study, we compared the histological and scintigraphic results of bone ingrowth into chambers having a congruently shaped interface that was moved 20 cycles/d with an amplitude of either 0.5 or 0.75 mm. Histological sections from both amplitude groups contained extensive new woven and trabecular bone, embedded in a fibrovascular network. However, the chambers with a larger amplitude of motion yielded less bone ingrowth than those with a smaller amplitude. These studies suggest that short, discrete periods of motion can stimulate the formation of fibrous tissue rather than bone using the parameters chosen in this model.

Abstract

Fifteen mature, New Zealand, female rabbits were divided into two groups. Using sterile technique, a 6-mm drill hole was made in the tibia 1 cm distal to the knee joint bilaterally. The marrow was scooped out underneath the hole. The right tibia received Simplex particulate cement polymer and the left leg functioned as a prepared, but nonimplanted, control. All animals were fed a standard diet. Whereas the six animals in Group 1 received regular water, the nine animals in Group 2 drank water in which sodium naproxen was dissolved (1.375 mg per ml). The animals were killed after 16 weeks. The implant area was harvested under sterile conditions and maintained in tissue culture. The cumulative collection of tissue culture supernatants over a three-day period was assayed for Prostaglandin E2 (PGE2) via radioimmunoassay. Specimens from Group 1 produced an average of 106.0 +/- 10.9 ng PGE2 on the right side, and 35.3 +/- 6.0 ng PGE2 on the left side. Specimens from Group 2 produced an average of 31.1 +/- 6.1 ng PGE2 on the right experimental side and 26.0 +/- 5.1 ng PGE2 on the left control side. The ratio of PGE2 values for the right divided by the left side yielded higher values in Group 1, compared to Group 2. Cement polymer particles have been shown to produce a florid foreign body histologic reaction similar to that associated with prosthetic loosening in man. This experiment has demonstrated that the increased PGE2 production by the membrane surrounding particulate cement polymer can be suppressed by the administration of an oral cyclo-oxygenase inhibitor. PGE2 has been previously shown to induce bone resorption in vivo and in vitro. The use of nonsteroidal antiinflammatory drugs may be indicated in retarding the bone loss associated with early prosthetic loosening.

Abstract

The purpose of this experiment was to determine whether mechanical overload of a single compartment of the knee in rabbits via proximal tibial osteotomy could produce early changes consistent with degenerative arthritis. Ten New Zealand white female rabbits were allocated into two groups. Group 1 (five animals) underwent a right 20 degrees valgus proximal tibial osteotomy to overload the lateral compartment of the knee. Group 2 (five animals) underwent a tibial osteotomy without malalignment (sham controls). The osteotomies were stabilized with a mini AO/ASIF plate and screws, allowing early mobilization. The left leg in each animal was left intact and served as a control. Animals were sacrificed after 3 months. Histological grading of the cartilage was performed according to Mankin et al. The mean histological gradings for the right minus the left knee were the same for the lateral and medial compartments in the 0 degrees sham osteotomy group. However, the mean histological grading of the "overloaded" lateral compartment was 2.4 times greater than the medial compartment in the 20 degrees valgus osteotomy group. These findings suggest that histological evidence of degenerative changes can be surgically induced in the rabbit knee by creating a biomechanical overload of one compartment.

Abstract

Fourteen mature female New Zealand White rabbits underwent implantation of Simplex polymethylmethacrylate (PMMA) powder or particulate (average 67 microns) ultrahigh-molecular-weight polyethylene (UHMWPE) through a drill hole in the proximal right tibia. The left tibia functioned as a prepared but nonimplanted control. Animals were killed after 16 weeks. Histological examination of the bone-implant interface in the particulate PMMA group disclosed a florid foreign-body reaction with the presence of giant cells and histiocytes. The particulate UHMWPE group demonstrated positively birefringent UHMWPE fragments, rimmed by foreign-body giant cells and histiocytes, embedded in a loose connective tissue stroma. UHMWPE interfaces were thicker and contained more histiocytes and fibrocytes; PMMA interfaces contained more marrow cells and lymphocytes. This study underscores the importance of biomaterial debris in the process of aseptic loosening of cemented joint arthroplasties.

Abstract

Twenty-eight mature New Zealand white female rabbits were allocated into 4 groups of 7 rabbits. Group 1 received a coiled wire of cobalt chrome alloy (Vitallium) (16 gauge x 1 cm). Group 2 received an equal weight of cobalt chrome particles averaging 15.4 microns in diameter. Group 3 received a coiled wire implant of commercially pure (C.P.) titanium (16 gauge x 1 cm). Group 4 received the same weight of C.P. titanium particles averaging 3.8 microns. The implants were placed through a drill hole in the proximal right tibia; the left tibia served as a prepared but nonimplanted control. The animals were killed after 16 weeks and quantitative histology was performed on undecalcified sections of the implant area. Bulk cobalt chrome and titanium implants were surrounded by a thin, incomplete, fibrous tissue layer with decreased numbers of cells. Trabeculae of bone were present within this connective tissue envelope. Fingerlike projections of bone enveloped the implant where it abutted endosteal bone. Clumped and loosely scattered cobalt chrome and titanium particles were surrounded by a minimal amount of fibrous connective tissue. Smaller particles were present within cells. Hematopoietic cells abutted the bulk or particulate implants directly. There was no evidence of acute or chronic inflammation or foreign body reaction. These results should be contrasted with those of Howie et al. in which intraarticular cobalt chrome particles stimulated a rapid proliferation of macrophages and synovial degeneration after 1 week. This may be due to a direct toxic effect of metals in an intra-articular environment, the smaller particle size used in that study, or to abrasive injury to the hyaline cartilage and subsequent synovitis. Our results underscore the general inert properties of these metals in the short term, when implanted into bone in the sizes and physical forms chosen.

Abstract

Fourteen mature New Zealand white female rabbits were allocated into two groups. Group 1 received a bolus doughy Simplex polymethylmethacrylate (PMMA) cement injected into the proximal tibia through a drill hole. Group 2 received an equal volume of particulate PMMA cement powder. The operated but nonimplanted left tibiae served as controls. The animals were killed after four months. The membrane surrounding the implant area was harvested aseptically and grown in tissue culture. The supernatants were assayed for prostaglandin E2 (PGE2) via radioimmunoassay. Bulk cement specimens produced on average 12.39 +/- 4.11 ng PGE2 on the right experimental side and 12.29 +/- 3.56 ng PGE2 on the left control side (not statistically different). Cement powder specimens produced 8.82 +/- 1.64 ng PGE2 on the right experimental side, which was statistically different from 4.21 +/- 0.88 ng PGE2 produced on the left control side. The ratio of PGE2 values for the right divided by the left side and the arithmetic difference between right and left sides were significantly higher in the particle group compared with the bulk group. Small, undigestable cement particles may be phagocytosed by foreign-body giant cells and histiocytes and then extruded into the extracellular compartment, along with substances such as PGE2. PGE2 has been implicated as the biologic mechanism for stimulating the bone lysis associated with prosthetic loosening.

Comparison of radiographic parameters for analysis of normal and dysplastic hips in the adult.Contemporary orthopaedicsGoodman, S. B.1990; 20 (5): 505-511

Abstract

Radiographic quantitation of the dysplastic hip in adults is difficult. This study compares the values for commonly used indices, the acetabular angle (AA), the center edge angle (CEA), and femoral head coverage, and the X-Y coordinate system on the anteroposterior pelvic radiograph in 30 adult patients with 60 normal hips, and 20 adult patients with 27 dysplastic hips. Dysplastic hips demonstrated significantly higher values for the AA and the X-Y coordinates, and significantly lower values for the CEA and femoral head coverage compared to normal hips. Femoral head coverage in dysplastic hips correlated best (negatively) with the Y coordinate, i.e., poorer coverage was associated with greater superior migration of the femoral head. The AA describes the slope of the acetabular roof, but does not take into account the relative position of the femoral head. The CEA measures the position of the femoral head in relation to the lateral lip of the acetabulum, but does not necessarily use the true acetabulum. The X-Y coordinate system relates the center of the femoral head to an identifiable acetabular landmark, the teardrop shadow. These coordinates are easily determined and can serve as an adjunct to other radiographic indices that quantitate the amount of subluxation in dysplastic hips in adults.

Abstract

This study examines the histological effects of different sizes of polyethylene particles implanted into the rabbit tibia. Seventeen mature New Zealand white female rabbits were allocated into three groups. Group 1 (5 rabbits) received polyethylene particles averaging approximately 16 microns in diameter, implanted into the right proximal tibia through a drill hole. Group 2 (5 animals) received particles averaging 26 microns, and Group 3 (7 rabbits) received particles averaging 67 microns. The left tibia was drilled but not implanted. Animals were sacrificed after 16 weeks. Histological analysis disclosed decreased hematopoietic activity within the left tibial drill hole. In all groups, the right tibia demonstrated positively birefringent polyethylene particles surrounded by, and within (smaller particles), histiocytes and giant cells in a fibrous tissue stroma. Statistical analysis disclosed more fibrocytes and less marrow cells at the interface of Group 3 (largest particles) compared to Group 1 and 2. Larger polyethylene particles, being less readily phagocytosed, appear to produce more fibrous encapsulation, compared to particles of a smaller size. The histological reaction stimulated by the different sizes of polyethylene particles resembled the membrane surrounding loose joint arthroplasties in humans.

Abstract

Differentiation of benign from pathologic compression fractures of vertebral bodies was evaluated with magnetic resonance imaging in a prospective study of 53 patients. Twenty-six patients had 34 benign posttraumatic compression fractures. Twenty-seven patients had metastatic disease to the vertebral column and seven pathologic fractures. T1- and T2-weighted spin-echo (SE) sequences (1.5 T) were performed in all patients. A presaturation technique was used to obtain "fat" and "water" images to better assess the degree of normal fatty marrow replacement in fractured vertebrae. Short inversion-time inversion-recovery (STIR) images were also obtained. Discrimination between benign and pathologic compression fractures was generally possible with the SE sequences. Chronic benign fractures demonstrated isointense marrow signal intensity (SI), compared with that of normal vertebrae with all sequences. Pathologic fractures showed low SI on T1-weighted images and high SI on T2-weighted images. Fat images revealed complete replacement of normal fatty marrow, shown as absent SI in the involved vertebral body. Water and STIR images showed diffuse high SI in pathologic fractures, with STIR images having the highest contrast between abnormal and normal marrow. Acute benign compression fractures also demonstrated high SI on T2-weighted, water, and STIR images, but the SI was less pronounced and the pattern was generally more inhomogeneous than that of pathologic compressions. In general, fat images showed only partial replacement of normal fatty marrow by low SI, in contrast to the complete absence of marrow SI typical of pathologic fractures.

Abstract

Three patients had compartment syndrome of the leg after tibial intramedullary nailing with reaming. They were all treated successfully with emergency fasciotomy. A prospective study was done of seven additional patients who had continual monitoring of the pressure in the deep posterior compartment during tibial intramedullary nailing with reaming. In five of them, the procedure was performed three weeks or less after injury and in the remaining two, the nailing was performed later for the treatment of non-union. Two pressure peaks in the deep posterior compartment were noted: one after strong longitudinal traction was applied and the fracture was reduced and the other during intramedullary reaming. Intraoperative pressure of thirty millimeters of mercury or more were recorded in three of the seven patients. In the treatment of tibial fractures, operative procedures that involve forceful traction for a long time may predispose the patient to compartment syndrome in the leg. Close clinical observation of such patients is needed. When there is a high risk of compartment syndrome, monitoring of the pressure in the compartment may be prudent.

Abstract

Clinical, radiographic and histologic findings are reported in a patient who underwent a hip shelf procedure 24 years previously. While the histologic observations confirm the presence of metaplasia of the surgically formed articular surface to fibrocartilage, there are superadded degenerative changes morphologically similar to those seen in degenerative arthritis.

Abstract

The purpose of this study was to investigate whether the salvage in the recovery room of blood from the drainage tubes of patients who had total joint arthroplasty was both feasible and efficacious. The cases of seventy-four patients who had seventy-six consecutive total hip or knee arthroplasties were studied prospectively. Intraoperative salvage of blood was performed using the Cell Saver. After closure of the fascial layer or joint capsule, the drainage tubes were connected to the Cell Saver in the operating room and remained connected in the recovery room for a mean of 2.9 hours. Blood that was collected in the recovery room was then processed and transfused back to the patient. The average amount of blood that was salvaged after different types of arthroplasty varied. The addition of bone cement to the acetabular side during primary total hip replacement decreased the amount of postoperative bleeding and of salvaged blood (p = 0.018), whereas cementing the femoral component had no statistically significant effect. Revision total hip replacement also resulted in more bleeding and in the collection of more blood in the recovery room than did primary total hip replacement (p = 0.03), especially if cement was not used (p less than 0.001). There were no statistical differences in the amount of blood that was collected in the recovery room after unilateral, bilateral, primary, or revision total knee replacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

The clinical and roentgenologic data from 31 excised components from 19 revision arthroplasty cases were correlated with the histology and biochemistry of the membrane at the bone-cement or bone-prosthesis interface. Twenty-seven components were cemented and four were uncemented. Twenty-four implants were clinically and roentgenologically loose, one was possibly loose, and six were well fixed. Loose components, whether cemented or not, demonstrated statistically higher prostaglandin E2 levels in the surrounding membrane compared to the nonloose group. Collagenase and M-collagenase levels were absent or insignificantly low in all specimens; no detectable interleukin 1 beta was found. This suggests that prostaglandin E2 may be associated with the bone lysis associated with prosthesis loosening.

Abstract

Five pelvises were photographed, roentgenographed, and sequentially sectioned or reamed to determine the location and appearance of the acetabular teardrop figure. The teardrop is located inferomedially in the acetabulum, just superior to the obturator foramen. The lateral lip is the exterior, and the medial lip is the interior of the acetabular wall. The ilioischial line projects over the medial acetabulum only fortuitously on the straight anteroposterior (AP) roentgenogram. Because of parallax, the relationship between the ilioischial line and the teardrop changes for views varying as little as 10 degrees in horizontal obliquity from the true AP roentgenogram. Because the teardrop comprises a well-defined, constant portion of the medial acetabular wall whereas the ilioischial line does not, the authors recommend using the acetabular teardrop rather than the ilioischial line for the detection and measurement of medial and superior acetabular migration.

Abstract

Twenty-one mature New Zealand white female rabbits were allocated into three groups of seven rabbits. Group I received a bolus of doughy Simplex polymethylmethacrylate (PMMA) cement injected into the proximal tibia through a drill hole. Group II received a preformed, cooled, bulk PMMA pellet. Group III had particulate PMMA powder implanted. The operated, but nonimplanted, left tibiae served as controls. Animals were killed after four months. Histologically, both Group I and Group II demonstrated a thin, fibrous tissue membrane at the implant interface. Particulate PMMA (Group III) stimulated a much thicker, florid, foreign body reaction composed of histiocytes and giant cells. The foreign body response to particulate acrylic cement was similar to that seen in failed cemented joint replacement arthroplasty in humans.

Abstract

Twenty-one infected total hip arthroplasties in 19 patients performed between 1971 and 1982 were prospectively followed, using a computerized standard orthopaedic arthritis record. These cases represent an inclusive and unselected, consecutive series. The mean follow-up period from time of infection was 4.8 years (range, 1.2-11.7 years). Infection was diagnosed by positive bacteriologic culture. Ten hips grew a staphylococcal species, 5 a single gram-negative organism, 1 a Streptococcus, and 5 multiple organisms. At final follow-up evaluation, only three hips (14%) had the previously infected prosthesis still in situ, and these had no evidence of ongoing deep infection. Five additional hips (24%) were successfully salvaged after one- or two-stage prosthetic exchange. Two hips (10%) have an infected prosthesis in situ. Eleven hips (52%) had resection arthroplasty, three after attempts at prosthetic reinsertion. Therefore, at final follow-up evaluation, only 8 of the 21 hips (38%) have an apparently infection-free salvaged or reinserted prosthesis in place. Good prognostic factors for prosthetic salvage/successful reinsertion include Staphylococcus epidermidis infection and a traumatic etiology necessitating later hip arthroplasty. Poor prognostic factors include infection with Staphylococcus aureus or multiple organisms and a preoperative diagnosis of avascular necrosis.

Abstract

Fourteen mature New Zealand white female rabbits underwent implantation of a bulk pellet and of particulate (less than 1,000 micron) ultra-high-molecular-weight polyethylene (UHMWPE), through a drill hole in the proximal right tibia. The left tibia served as a drilled but nonimplanted control. The rabbits were killed after 16 weeks. Histologic examination of the bone-implant interface in the bulk UHMWPE group disclosed a fibrous tissue membrane with infrequent giant cell and histiocytic clusters at surface irregularities. The particulate group demonstrated positively birefringent UHMWPE fragments, rimmed by foreign body giant cells and histiocytes, embedded in a loose connective tissue. The histologic response to particulate UHMWPE is similar to that seen surrounding loose total joint arthroplasties in humans.

Abstract

We reviewed early and late motion changes of the hip in 102 hemophiliacs with a mean follow-up of 7 years. Sixty patients (59%) had at least one hip bleed. Sixty-four hips in 49 patients demonstrated at least a 15 degree change in range of motion (ROM) at some time. At final review, only 34 of these 64 hips (53%) lost motion. Patients whose hips lost motion were just as likely to report hip bleeds as those who lost no motion. Twenty hips examined within 2 months of bleeding lost significant motion, but most motion returned within a year. The relationship between hip girdle bleeding and ROM remains obscure.

Abstract

The radiographs of 97 patients (117 hips) who had a straight-stem Muller femoral component and a non-metal-backed acetabular component were reviewed to determine whether the mode of acetabular loosening predicted by finite element stress analysis (FESA) is observed clinically. The follow-up period averaged 3.1 years (range, 2.0-4.6 years). Significantly more lucent lines were present in zones 1 and 3, compared with zone 2 (P less than .01). This finding corroborates the predictions of FESA and suggests that the production of acetabular lucent lines is due in part to chronic mechanical overload.

Conference Proceedings

Abstract

Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown.We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups.Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

Abstract

Cages provide a scaffold for restoration of bone stock in revision arthroplasty of the acetabulum. A major problem with cages is failure at 5 to 10 years due to loss of fixation. The present generation of cages are not made of a material that provides biologic fixation. Trabecular metal cups provide excellent biologic fixation and a favorable environment for bone graft remodeling. For large bone defects where there is not optimal contact with host bone at the correct anatomic level, a trabecular cup is placed against bone graft, fixed with screws, and protected by a cage into which the polyethylene cup is cemented. The initial stability is via the cage, but when graft remodeling takes place, the stress will be taken by the trabecular metal relieving the stress on the cage.

The current role of structural grafts and cages in revision arthroplasty of the hipGross, A. E., Goodman, S.SPRINGER.2004: 193-200

Abstract

Treating large segmental acetabular defects that comprise more than 50% of the acetabulum is one of the most difficult challenges in revision arthroplasty of the hip. One of the surgical options is a structural acetabular allograft. Unless these allografts are protected by a cage that extends from ilium to ischium, there is an unacceptable incidence of graft failure. The cage allows reconstruction at the correct anatomic level. It provides a scaffold for bone grafting (structural and morsellized). The use of cement to stabilize the cup allows the surgeon to adjust the cup position independent of the cage. The current generation of cages does not provide biologic fixation and with time may loosen or fracture. Recent experience with a combination of a trabecular metal shell protected by a cage may offer a more favorable environment for bone grafting with permanent biologic fixation of the cup cage construct.

Abstract

The outcome of total joint arthroplasty is determined by biological events at the bone-implant interface. Macrophages phagocytose implant or wear debris at the interface and release proinflammatory mediators such as interleukins 1 and 6, tumor necrosis factor-alpha, and prostaglandin E2. These mediators are thought to contribute to the resorption of periprosthetic bone. Previous studies of tissues harvested from the bone-implant interface of failed orthopaedic implants demonstrated a possible role for two other cytokines, granulocyte-macrophage colony-stimulating factor and interleukin-4. The present study examined the effects of in vitro challenge with polymethylmethacrylate particles on the expression of granulocyte-macrophage colony-stimulating factor by primary human monocytes/macrophages and the role of interleukin-4 in regulating this expression. The polymethylmethacrylate particles caused a dose-dependent release of granulocyte-macrophage colony-stimulating factor at 48 hours. This release was accompanied by increased expression of interleukins 6 and 1beta and tumor necrosis factor-alpha. Release of the lysosomal enzyme hexosaminidase also increased in response to the particles. Interleukin-4 inhibited the expression of granulocyte-macrophage colony-stimulating factor, interleukin-6, and tumor necrosis factor-alpha at 48 hours in a dose-dependent manner. The data presented in this study confirm the hypothesis that interleukin-4 downregulates particle-induced activation of macrophages, as demonstrated by the decreased release of proinflammatory mediators.

Abstract

Twenty-nine mature New Zealand white, female rabbits were divided into four groups. Using sterile technique, a 6 mm drill hole was made in the tibia 1 cm distal to the knee joint. The marrow was scooped out underneath the hole. The right tibia received Simplex particulate cement polymer (PMMA) (groups 1 and 2) or polyethylene particles (UHMWP) (groups 3 and 4). The left leg functioned as a prepared but non-implanted control. All animals were fed a standard diet; those in groups 1 and 3 received plain water, while groups 2 and 4 drank water in which sodium naproxen was dissolved (1.375 mg/ml). Animals were killed after 16 wk. The implant area was harvested and grown in tissue culture. The cumulative collection of tissue culture supernatants over 3 d was assayed for prostaglandin E2 (PGE2) via radioimmunoassay. PGE2 production was significantly higher in the membrane harvested from the right side containing particulate cement with no sodium naproxen (group 1) compared with controls (P less than 0.05). The ratio of PGE2 values for the right divided by the left side yielded higher values in group 1, compared with groups 2, 3 or 4 (P less than 0.01). Previous studies have suggested that particulate debris and PGE2 production are associated with arthroplasty loosening. This experiment has demonstrated that PGE2 production by the membrane surrounding particulate debris can be suppressed by the administration of oral sodium naproxen. Because non-steroidal anti-inflammatory drugs are known to inhibit prostaglandin synthesis in man, these agents may prove useful in retarding the bone loss associated with early prosthetic loosening.